Quinoline-indole antimicrobial agents, uses and compositions related thereto

ABSTRACT

The present invention provides methods and pharmaceutical preparations that inhibit the growth of bacterial microorganisms. Additionally, the present invention provides methods and pharmaceutical preparations that kill bacterial microorganisms.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 09/045,051,filed Mar. 19, 1998, which is a continuation-in-part of U.S. Ser. No.08/878,781, filed Jun. 19, 1997 now abandoned.

BACKGROUND OF THE INVENTION

A number of structural classes of compounds with antibacterialproperties are known. Historically, the most important classes ofantibacterials have been the β-lactams, macrolides, lincosamides,aminoglycosides, tetracyclines, polypeptides, and sulfonamides. The bulkof these antibacterial compounds were isolated originally from molds,fungi or bacteria; synthetic and semi-synthetic compounds, additionally,have proven to be efficacious in the treatment of bacterial infections.In the broadest possible sense, known antibacterials work by influencingat least one of the following cellular processes or characteristics:cell wall synthesis; protein synthesis; nucleic acid synthesis; cellularmetabolism; and cytoplasmic membrane permeability. Brief descriptionsfollow of the mechanisms of action of members of each of theaforementioned classes of antibacterials.

The β-lactam antibiotics inhibit penicillin binding proteins (PBPs). ThePBPs are ubiquitous bacterial enzymes that are involved in cell wallbiosynthesis (reviewed in Waxman et al., 1983 Annual Review ofBiochemistry 58:825-869; Georgopapadkou et al., 1983 Handbook ofExperimental Pharmacology 67:1-77; and Ghuysen, 1991 Annual Review ofMicrobiology 45:37-67); inhibition of these proteins disrupts thebiosynthesis of the bacterial cell wall. Specifically, these compoundsact as substrate analogs for the PBPs and form an acyl enzymeintermediate. This acyl enzyme intermediate is resistant to subsequenthydrolysis and ties up the enzyme in a relatively long-lived inactiveform. Bacteria have responded to the widespread use of β-lactamantibiotics by evolving a class of β-lactam hydrolyzing enzymes known asβ-lactamases. These enzymes are one of the sources of drug resistancenow being observed in a number of bacterial diseases includingtuberculosis, malaria, pneumonia, meningitis, dysentery, bacteremia, andvarious venereal diseases.

The macrolides are a family of antibiotics whose structures containlarge lactone rings linked through glycoside bonds with amino sugars.The most important members of the group are erythromycin andoleandomycin. Erythromycin is active against most Gram-positivebacteria, Neisseria, Legionella and Haemophilus, but not against theEnterobacteriaceae. Macrolides inhibit bacterial protein synthesis bybinding to the 50S ribosomal subunit. Binding inhibits elongation of theprotein by peptidyl transferase or prevents translocation of theribosome or both. Macrolides are bacteriostatic for most bacteria butare bactericidal for a few Gram-positive bacteria.

The lincosamides are sulfur-containing antibiotics isolated fromStreptomyces lincolnensis. There are two important lincosamides:lincomycin and clindamycin. Clindamycin is preferred over lincomycin dueto its greater potency, fewer adverse side effects, and its morefavorable pharmacokinetic properties. Bacterial resistance and crossresistance to clindamycin have begun to emerge. The lincosamides areactive against Gram-positive bacteria especially cocci, but alsonon-spore forming anaerobic bacteria, Actinomycetes, Mycoplasm and somePlasmodium. The lincosamides bind to the 50S ribosomal subunit andthereby inhibit protein synthesis. These drugs may be bacteriostatic orbactericidal depending upon several factors, including their localconcentration.

Aminoglycosides are important antibacterials used primarily to treatinfections caused by susceptible aerobic Gram-negative bacteria.Unfortunately, they have a narrow margin of safety, producingcharacteristic lesions in kidney, cochlea, and vestibular apparatuswithin the therapeutic dose range. Because they are polycations, theaminoglycosides cross cellular membranes very poorly.

The tetracyclines consist of eight related antibiotics which are allnatural products of Streptomyces, although some can now be producedsemi-synthetically. Tetracycline, chlortetracycline and doxycycline arethe best known members of this class. The tetracyclines arebroad-spectrum antibiotics with a wide range of activity against bothGram-positive and Gram-negative bacteria. The tetracyclines act byblocking the binding of aminoacyl tRNA to the A site on the ribosome.Tetracyclines inhibit protein synthesis on isolated 70S or 80S(eukaryotic) ribosomes, and in both cases, their effect is on the smallribosomal subunit. Most bacteria possess an active transport system fortetracycline that will allow intracellular accumulation of theantibiotic at concentrations 50 times as great as that in thesurrounding medium. This system greatly enhances the antibacterialeffectiveness of tetracycline and accounts for its specificity ofaction, since an effective concentration is not accumulated in hostcells. Thus a blood level of tetracycline which is harmless to mammaliantissues can halt protein synthesis in invading bacteria. Thetetracyclines have a remarkably low toxicity and minimal side effects inmammals. The combination of their broad spectrum and low toxicity hasled to their overuse and misuse by the medical community and thewide-spread development of resistance has reduced their effectiveness.Nonetheless, tetracyclines still have some important uses, such as inthe treatment of Lyme disease.

The polypeptide antibacterials have in common their basic structuralelements—amino acids. Representatives of this class include vancomycin,and bacitracin. Vancomycin can be used to treat both systemic andgastrointestinal infections, whereas because of serious systemictoxicities bacitracin, is limited to topical applications. Vancomycininhibits bacterial cell wall synthesis by inhibiting peptidoglycansynthase, apparently by binding to D-alanyl-D-alanine, a component ofthe cross-link between chains. This action inhibits peptidoglycan chainelongation, and as might be expected, the effect is bactericidal formost organisms if they are dividing rapidly. Because it does not targetpenicillin-binding enzymes, vancomycin is not cross-resistant with theβ-lactams. Bacitracin is a narrow spectrum antibiotic which inhibitscell wall biosynthesis by inhibiting lipid pyrophosphatase; this enzymeis involved in transmembrane transport of peptidoglycan precursors.

The sulphonamides are usually bacteriostatic and arrest cell growth byinhibiting bacterial folic acid synthesis. They are effective againstsensitive strains of Gram-negative and Gram-positive bacteria,Actinomyces, Nocardia and Plasmodia. However, extensive clinical use ofsulfonamides over many years has resulted in a high level of resistanceand their current use is limited.

Additionally, there are miscellaneous antibacterials that do not fitreadily into the structural classes outlined above. A comprehensivediscussion of these miscellaneous antibacterials is not warranted; asmall number of antibacterials in this group, however, are relevant tothe subject compounds. First, U.S. Pat. No. 3,799,929 “Cinchoninic AcidDerivatives”, granted to Eli Lilly and Company on Mar. 26, 1974, andU.S. Pat. No. 3,870,712 “Cinchoninic Acid Derivatives”, granted to EliLilly and Company on Mar. 11, 1975, are directed to sets of substitutedquinolines represented by structure A. Of particular relevance to thesubject compounds, Lilly claims compounds represented by A wherein: 1) Rrepresents 3-indolyl or 1-methyl-3-indolyl; and 2) R₁ represents —OH orloweralkoxy of 1 to 3 carbons.

Moreover, a few quinoline-indole compounds have been found to displaybiological activity other than against bacteria. Published PCTapplications WO 95/32948 “Quinoline Derivatives as Tachykinin NK₃Receptor Antagonists”, and WO 96/02509 “Quinoline Derivatives as NK₃Antagonists”, filed by SmithKline Beecham disclose substitutedquinolines represented by structures B and C, respectively. In WO95/32948, SmithKline Beecham claims compounds represented by Bwherein: 1) R₅ is branched or linear C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkylalkyl, optionally substituted aryl, or an optionallysubstituted single or fused ring heterocyclic group, having aromaticcharacter, containing from 5 to 12 ring atoms and comprising up to fourhetero-atoms in the or each ring selected from S, O, N; and 2) X is O,S, or N—CN. In WO 96/02509, SmithKline Beecham claims compoundsrepresented by C wherein: 1) Ar is an optionally substituted phenyl ornaphthyl group or an optionally substituted single or fused ringheterocyclic group, having aromatic character, containing from 5 to 12ring atoms and comprising up to four hetero-atoms in the or each ringselected from S, O, N; and 2) X is O, S, H₂ or N—CN.

Antibacterial resistance is a global clinical and public health problemthat has emerged with alarming rapidity in recent years and undoubtedlywill increase in the near future. Resistance is a problem in thecommunity as well as in health care settings, where transmission ofbacteria is greatly amplified. Because multiple drug resistance is agrowing problem, physicians are now confronted with infections for whichthere is no effective therapy. The morbidity, mortality, and financialcosts of such infections pose an increasing burden for health caresystems worldwide, but especially in countries with limited resources.Strategies to address these issues emphasize enhanced surveillance ofdrug resistance, increased monitoring and improved usage ofantimicrobial drugs, professional and public education, development ofnew drugs, and assessment of alternative therapeutic modalities.

SUMMARY OF THE INVENTION

There exists a need to provide alternative and improved agents for thetreatment of bacterial infections particularly for the treatment ofinfections caused by resistant strains of bacteria, e.g.penicillin-resistant, methicillin-resistant, ciprofloxacin-resistant,and/or vancomycin-resistant strains, as well as for the decontaminationof objects bearing such organisms, e.g. non-living matter, hospitalequipment, walls of operating rooms, and the like.

In general, the present invention provides a method and pharmaceuticalpreparations for inhibiting the growth of bacterial microorganisms, suchas in the treatment of Gram-positive infections, includingStaphylococcus infections, Streptococcus infections, and Enterococcusinfections, and in the treatment of Gram-negative infections, includingEnterobacteriaceae infections, Mycobacterium infections, Neisseriainfections, Pseudomonas infections, Shigella infections, Escherichiainfections, Bacillus infections, Micrococcus infections, Arthrobacterinfections, and Peptostreptococcus infections. For instance, thecompounds of the present invention are particularly useful in thetreatment of infections caused by methicillin-resistant strains ofbacteria, e.g., methicillin-resistant strains of Staphylococcus aureus(MRSA; Micrococcus pyogenes var. aureus), and ciprofloxacin-resistantstrains of bacteria, e.g., ciprofloxacin-resistant strains ofStaphylococcus aureus (CRSA). In preferred embodiments, the presentinvention can be used to inhibit bacterial infections caused byGram-positive bacteria, for example, S. aureus, S. epidermidis, S.pneumonia.

The invention, as described herein, is directed to the use of small(e.g., M_(r)<1.5 kD) organic molecules, e.g., 2-(3-indolyl)-quinolinesand substituted derivatives thereof, and pharmaceutical formulationsthereof, in the treatment of bacterial infections. Specifically proposedas antibacterial agents are compounds based on2-(3-indolyl)-4-quinolinecarboxamide and derivatives thereof, and2-(3-indolyl)quinoline, and derivatives thereof. As described herein,many of the antibacterials have in vitro minimum inhibitoryconcentrations (MICs) at or below single-digit micromolar concentrationsin assays against cultures of methicillin-resistant Staphylococcusaureus (MRSA), ciprofloxacin-resistant Staphylococcus aureus (CRSA),vancomycin-resistant Enterococcus spp. (VRE), and/orpenicillin-resistant Pseudomonas (PRP). The wide range of antibacterialcompounds disclosed herein enables the potential to tailor potency,specificity, solubility, bioavailability, stability, toxicity, and otherphysical properties to suit specific purposes.

DETAILED DESCRIPTION OF THE INVENTION

In the last decade, the frequency and spectrum ofantimicrobial-resistant infections has increased. Certain infectionsthat are essentially untreatable are reaching epidemic proportions inboth the developing world and institutional settings in the developedworld. Antimicrobial resistance is manifested in increased morbidity,mortality, and health-care costs. Staphylococcus aureus is ansignificant cause of nosocomial infection, especially nosocomialpneumonia, surgical wound infection, and bloodstream infection (Panlihoet al., Infect. Cont. Hosp. Epidemiol. 13: 582-586 (1992)). Otherpathogens commonly associated with nosocomial infection include, but arenot limited to, Escherichia coli, Pseudomonas aeruginosa, Enterococcusspp., Enterobacter spp., coagulase-negative staphylococci (CNS). Asdescribed above, a considerable amount of effort has been devoted todeveloping bacteriostatic and bactericidal agents with activity againstthese and other microorganisms.

The present invention relates to heterocyclic antibacterial agents withantimicrobial activity, and particularly, antibacterial activity againstboth sensitive and resistant strains. The subject antibacterialcompounds comprise two distinct heterocycles that are covalently linkedto each other, preferably via a carbon-carbon single bond. In preferredembodiments, the individual heterocyclic moieties are quinoline andindole nuclei interconnected at their respective 2- and 3-positions.Three preferred subclasses of the compounds are disclosed: 1) a subclassin which the substituent at the 4-position of the quinoline nucleuscomprises a primary or secondary amine; 2) a subclass in which thesubstituent at the 4-position of the quinoline nucleus is a hydrogen,halogen, or another group that does not comprise a primary or secondaryamine; and 3) a subclass in which a substituent on the B-ring of thequinoline nucleus is a 1-alkynyl group. The remaining positions of the2-quinolinyl and 3-indolyl nuclei of the subject compounds mayindependently be unsubstituted or substituted with a variety of groupsgiving rise to a variety of antimicrobial compounds.

For example, in one embodiment, the compounds of the present inventionare represented by the general formula 1, or a pharmaceuticallyacceptable salt and/or prodrug thereof:

wherein

each of A and B independently represent fused rings selected from agroup consisting of monocyclic or polycyclic cycloalkyls, cycloalkenyls,aryls, and heterocyclic rings, said rings comprising from 4 to 8 atomsin a ring structure;

X represents CR, N, N(O), P, or As;

Y represents CR₂, NR, O, PR, S, AsR, or Se;

R, R₁, R₂, and R₃, for each occurrence, independently representhydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy,amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl,phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride,silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone,aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal,ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate,epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide,thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀;

R₄ and R₅, for each occurrence, independently represent halogen, alkyl,alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl,alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl,carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl,arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl,nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl,heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R₈₀;

A and B independently may be unsubstituted or substituted with R₄ andR₅, respectively, any number of times up to the limitations imposed bystability and the rules of valence;

R₁ and R₃ taken together may represent a ring comprising a total of 3-7atoms in the backbone of said ring; said ring may comprise one or twoheteroatoms in its backbone; and said ring may bear additionalsubstituents or be unsubstituted;

R₈₀ represents an unsubstituted or substituted aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle; and

m is an integer in the range 0 to 8 inclusive.

These compounds are effective against a number of human and veterinarypathogens, including Gram-positive bacteria such as multiply-resistantstaphylococci, streptococci and enterococci, and are expected to beactive against Gram-negative organisms as well, such as Bacteroides spp.and Clostridia spp. species, and acid-fast organisms such asMycobacterium tuberculosis, Mycobacterium avium and other Mycobacteriumspp., and in organisms such as Mycoplasma spp. It is contemplated thatthe compounds of the invention can be used in combating and/oreliminating an infectious process caused by a microorganism in a host.In a particular aspect of the invention, the high potency and rapidbactericidal activity of these compounds make them attractive candidatesfor use in preventative therapies, such as sterilization of wounds priorto suture, as well as the sterilization of instruments prior to theiruse in surgical or other invasive procedures.

The invention is also directed to methods for treating a microbialinfection in a host using the compositions of the invention. Forinstance, the subject method can be used to treat or prevent nosocomialbacteremia and skin/wound infection, or lower respiratory infection,endocarditis, and infections of the urinary tract. According to thepresent invention, treatment of such bacterial diseases comprises theadministration of a pharmaceutical composition of the invention in atherapeutically effective amount to an individual in need of suchtreatment. The compositions may be administered parenterally byintramuscular, intravenous, intraocular, intraperitoneal, orsubcutaneous routes; inhalation; orally, topically and intranasally.

Their antimicrobial activity also renders the compounds of the inventionparticularly useful in inhibiting unwanted microbial growth in tissueculture, especially those used for production of recombinant proteins orvectors for use in gene therapy.

The invention is also directed to pharmaceutical compositions,comprising one or more of the antimicrobial compounds of the inventionas the active ingredient(s), which may be administered to a host animal.

I. Definitions

For convenience, certain terms employed in the specification, examples,and appended claims are collected here.

As used herein, the term “antimicrobial” refers to the ability of thecompounds of the invention to prevent, inhibit or destroy the growth ofmicrobes such as bacteria, fungi, protozoa and viruses.

The terms “quinoline” and “indole” are intended to mean compounds havingthe following general chemical structures, wherein the numbers aroundtheir peripheries indicate the art recognized positional designationsfor the two ring systems, and the capital letters contained within theindividual rings are, likewise, their art recognized descriptors:

An analog of a quinoline or indole is intended to mean any derivative ofa quinoline or indole, in particular derivatives that adhere to therules of valence in which a nitrogen is replaced by another atom,derivatives in which any of the carbon atoms are replaced with anotherheavy atom, and derivatives in which additional chemical groups areattached to any of the heavy atoms of the molecule. For example, thepresent invention contemplates the use of derivatives of4-quinolinecarboxylic acid, quinazoline and 1H-indazole:

The term “prodrug” is intended to encompass compounds which, underphysiological conditions, are converted into the antibacterial agents ofthe present invention. A common method for making a prodrug is to selectmoieties, e.g., for any of the R₁-R₅ substituents of formula 1, whichare hydrolyzed under physiological conditions to provide the desired. Inother embodiments, the prodrug is converted by an enzymatic activity ofthe host animal or the target bacteria.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are boron, nitrogen,oxygen, phosphorus, sulfur and selenium.

The term “electron-withdrawing group” is recognized in the art, anddenotes the tendency of a substituent to attract valence electrons fromneighboring atoms, i.e., the substituent is electronegative with respectto neighboring atoms. A quantification of the level ofelectron-withdrawing capability is given by the Hammett sigma (σ)constant. This well known constant is described in many references, forinstance, J. March, Advanced Organic Chemistry, McGraw Hill BookCompany, New York, (1977 edition) pp. 251-259. The Hammett constantvalues are generally negative for electron donating groups (σ[P]=−0.66for NH₂) and positive for electron withdrawing groups (σ[P]=0.78 for anitro group), σ[P] indicating para substitution. Exemplaryelectron-withdrawing groups include nitro, acyl, formyl, sulfonyl,trifluoromethyl, cyano, chloride, and the like. Exemplaryelectron-donating groups include amino, methoxy, and the like.

Herein, the term “aliphatic group” refers to a straight-chain,branched-chain, or cyclic aliphatic hydrocarbon group and includessaturated and unsaturated aliphatic groups, such as an alkyl group, analkenyl group, and an alkynyl group.

The term “alkyl” refers to the radical of saturated aliphatic groups,including straight-chain alkyl groups, branched-chain alkyl groups,cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, andcycloalkyl substituted alkyl groups. In preferred embodiments, astraight chain or branched chain alkyl has 30 or fewer carbon atoms inits backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀ for branchedchain), and more preferably 20 or fewer. Likewise, preferred cycloalkylshave from 3-10 carbon atoms in their ring structure, and more preferablyhave 5, 6 or 7 carbons in the ring structure.

Moreover, the term “alkyl” (or “lower alkyl”) as used throughout thespecification, examples, and claims is intended to include both“unsubstituted alkyls” and “substituted alkyls”, the latter of whichrefers to alkyl moieties having substituents replacing a hydrogen on oneor more carbons of the hydrocarbon backbone. Such substituents caninclude, for example, a halogen, a hydroxyl, a carbonyl (such as acarboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (suchas a thioester, a thioacetate, or a thioformate), an alkoxyl, aphosphoryl, a phosphonate, a phosphinate, an amino, an amido, anamidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, analkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, asulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromaticmoiety. It will be understood by those skilled in the art that themoieties substituted on the hydrocarbon chain can themselves besubstituted, if appropriate. For instance, the substituents of asubstituted alkyl may include substituted and unsubstituted forms ofamino, azido, imino, amido, phosphoryl (including phosphonate andphosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl andsulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls(including ketones, aldehydes, carboxylates, and esters), —CF₃, —CN andthe like. Exemplary substituted alkyls are described below. Cycloalkylscan be further substituted with alkyls, alkenyls, alkoxys, alkylthios,aminoalkyls, carbonyl-substituted alkyls, —CF₃, —CN, and the like.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group (e.g., an aromatic or heteroaromatic group).

The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but that contain at least one double or triple bond respectively.

Unless the number of carbons is otherwise specified, “lower alkyl” asused herein means an alkyl group, as defined above, but having from oneto ten carbons, more preferably from one to six carbon atoms in itsbackbone structure. Likewise, “lower alkenyl” and “lower alkynyl” havesimilar chain lengths. Throughout the application, preferred alkylgroups are lower alkyls. In preferred embodiments, a substituentdesignated herein as alkyl is a lower alkyl.

The term “aryl” as used herein includes 5-, 6- and 7-memberedsingle-ring aromatic groups that may include from zero to fourheteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazineand pyrimidine, and the like. Those aryl groups having heteroatoms inthe ring structure may also be referred to as “aryl heterocycles” or“heteroaromatics.” The aromatic ring can be substituted at one or morering positions with such substituents as described above, for example,halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl,alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic orheteroaromatic moieties, —CF₃, —CN, or the like. The term “aryl” alsoincludes polycyclic ring systems having two or more cyclic rings inwhich two or more carbons are common to two adjoining rings (the ringsare “fused rings”) wherein at least one of the rings is aromatic, e.g.,the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls,aryls and/or heterocyclyls.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl,phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl and methanesulfonyl, respectively. A morecomprehensive list of the abbreviations utilized by organic chemists ofordinary skill in the art appears in the first issue of each volume ofthe Journal of Organic Chemistry; this list is typically presented in atable entitled Standard List of Abbreviations. The abbreviationscontained in said list, and all abbreviations utilized by organicchemists of ordinary skill in the art are hereby incorporated byreference.

The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstitutedbenzenes, respectively. For example, the names 1,2-dimethylbenzene andortho-dimethylbenzene are synonymous.

The terms “heterocyclyl” or “heterocyclic group” refer to 3- to10-membered ring structures, more preferably 3- to 7-membered rings,whose ring structures include one to four heteroatoms. Heterocycles canalso be polycycles. Heterocyclyl groups include, for example, thiophene,thianthrene, furan, pyran, isobenzofuran, chromene, xanthene,phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole,pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole,indole, indazole, purine, quinolizine, isoquinoline, quinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine,phenanthroline, phenazine, phenarsazine, phenothiazine, furazan,phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine,piperazine, morpholine, lactones, lactams such as azetidinones andpyrrolidinones, sultams, sultones, and the like. The heterocyclic ringcan be substituted at one or more positions with such substituents asdescribed above, as for example, halogen, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido,phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio,sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic orheteroaromatic moiety, —CF₃, —CN, or the like.

The terms “polycyclyl” or “polycyclic group” refer to two or more rings(e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/orheterocyclyls) in which two or more carbons are common to two adjoiningrings, e.g., the rings are “fused rings”. Rings that are joined throughnon-adjacent atoms are termed “bridged” rings. Each of the rings of thepolycycle can be substituted with such substituents as described above,as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromaticmoiety, —CF₃, —CN, or the like.

The term “carbocycle”, as used herein, refers to an aromatic ornon-aromatic ring in which each atom of the ring is carbon.

As used herein, the term “nitro” means —NO₂; the term “halogen”designates —F, —Cl, —Br or —I; the term “sulfhydryl” means —SH; the term“hydroxyl” means —OH; and the term “sulfonyl” means —SO₂—.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety that can berepresented by the general formula:

wherein R₉, R₁₀ and R′₁₀ each independently represent a hydrogen, analkyl, an alkenyl, —(CH₂)_(m)—R80, or R₉ and R₁₀ taken together with theN atom to which they are attached complete a heterocycle having from 4to 8 atoms in the ring structure; R80 represents an aryl, a cycloalkyl,a cycloalkenyl, a heterocycle or a polycycle; and m is zero or aninteger in the range of 1 to 8. In preferred embodiments, only one of R₉or R₁₀ can be a carbonyl, e.g., R₉, R₁₀ and the nitrogen together do notform an imide. In even more preferred embodiments, R₉ and R₁₀ (andoptionally R′₁₀) each independently represent a hydrogen, an alkyl, analkenyl, or —(CH₂)_(m)—R80. Thus, the term “alkylamine” as used hereinmeans an amine group, as defined above, having a substituted orunsubstituted alkyl attached thereto, i.e., at least one of R₉ and R₁₀is an alkyl group.

The term “acylamino” is art-recognized and refers to a moiety that canbe represented by the general formula:

wherein R₉ is as defined above, and R′₁₁ represents a hydrogen, analkyl, an alkenyl or —(CH₂)_(m)— R80, where m and R80 are as definedabove.

The term “amido” is art recognized as an amino-substituted carbonyl andincludes a moiety that can be represented by the general formula:

wherein R₉, R₁₀ are as defined above. Preferred embodiments of the amidewill not include imides which may be unstable.

The term “alkylthio” refers to an alkyl group, as defined above, havinga sulfur radical attached thereto. In preferred embodiments, the“alkylthio” moiety is represented by one of —S— alkyl, —S-alkenyl,—S-alkynyl, and —S—(CH₂)_(m)—R80, wherein m and R₈₀ are defined above.Representative alkylthio groups include methylthio, ethyl thio, and thelike.

The term “carbonyl” is art recognized and includes such moieties as canbe represented by the general formula:

wherein X is a bond or represents an oxygen or a sulfur, and R₁₁represents a hydrogen, an alkyl, an alkenyl, —(CH₂)_(m)—R₈₀ or apharmaceutically acceptable salt, R′₁₁ represents a hydrogen, an alkyl,an alkenyl or —(CH₂)_(m)—R₈₀, where m and R₈₀ are as defined above.Where X is an oxygen and R₁₁ or R′₁₁ is not hydrogen, the formularepresents an “ester”. Where X is an oxygen, and R₁₁ is as definedabove, the moiety is referred to herein as a carboxyl group, andparticularly when R₁₁ is a hydrogen, the formula represents a“carboxylic acid”. Where X is an oxygen, and R′₁₁ is hydrogen, theformula represents a “formate”. In general, where the oxygen atom of theabove formula is replaced by sulfur, the formula represents a“thiolcarbonyl” group. Where X is a sulfur and R₁₁ or R′₁₁ is nothydrogen, the formula represents a “thiolester.” Where X is a sulfur andR₁₁ is hydrogen, the formula represents a “thiolcarboxylic acid.” WhereX is a sulfur and R₁₁′ is hydrogen, the formula represents a“thiolformate.” On the other hand, where X is a bond, and R₁₁ is nothydrogen, the above formula represents a “ketone” group. Where X is abond, and R₁₁ is hydrogen, the above formula represents an “aldehyde”group.

The terms “alkoxyl” or “alkoxy” as used herein refers to an alkyl group,as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as can berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl,—O—(CH₂)_(m)—R₈₀, where m and R₈₀ are described above.

The term “sulfonate” is art recognized and includes a moiety that can berepresented by the general formula:

in which R₄₁ is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized andrefer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl,and nonafluorobutanesulfonyl groups, respectively. The terms triflate,tosylate, mesylate, and nonaflate are art-recognized and refer totrifluoromethanesulfonate ester, p-toluenesulfonate ester,methanesulfonate ester, and nonafluorobutanesulfonate ester functionalgroups and molecules that contain said groups, respectively.

The term “sulfate” is art recognized and includes a moiety that can berepresented by the general formula:

in which R₄₁ is as defined above.

The term “sulfonamido” is art recognized and includes a moiety that canbe represented by the general formula:

in which R₉ and R′₁₁ are as defined above.

The term “sulfamoyl” is art-recognized and includes a moiety that can berepresented by the general formula:

in which R₉ and R₁₀ are as defined above.

The terms “sulfoxido” or “sulfinyl”, as used herein, refers to a moietythat can be represented by the general formula:

in which R₄₄ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.

A “phosphoryl” can in general be represented by the formula:

wherein Q₁ represented S or O, and R₄₆ represents hydrogen, a loweralkyl or an aryl. When used to substitute, e.g., an alkyl, thephosphoryl group of the phosphorylalkyl can be represented by thegeneral formula:

wherein Q₁ represented S or O, and each R₄₆ independently representshydrogen, a lower alkyl or an aryl, Q₂ represents O, S or N. When Q₁ isan S, the phosphoryl moiety is a “phosphorothioate”.

A “phosphoramidite” can be represented in the general formula:

wherein R₉ and R₁₀ are as defined above, and Q₂ represents O, S or N.

A “phosphonamidite” can be represented in the general formula:

wherein R₉ and R₁₀ are as defined above, Q₂ represents O, S or N, andR₄₈ represents a lower alkyl or an aryl, Q₂ represents O, S or N.

A “selenoalkyl” refers to an alkyl group having a substituted selenogroup attached thereto. Exemplary “selenoethers” which may besubstituted on the alkyl are selected from one of —Se-alkyl,—Se-alkenyl, —Se-alkynyl, and —Se—(CH₂)_(m)—R₈₀, m and R₈₀ being definedabove.

Analogous substitutions can be made to alkenyl and alkynyl groups toproduce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls,amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls,carbonyl-substituted alkenyls or alkynyls.

As used herein, the definition of each expression, e.g. alkyl, m, n,etc., when it occurs more than once in any structure, is intended to beindependent of its definition elsewhere in the same structure. Certaincompounds of the present invention may exist in particular geometric orstereoisomeric forms. The present invention contemplates all suchcompounds, including cis- and trans-isomers, R- and S-enantiomers,diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof,and other mixtures thereof, as falling within the scope of theinvention. Additional asymmetric carbon atoms may be present in asubstituent such as an alkyl group. All such isomers, as well asmixtures thereof, are intended to be included in this invention.

If, for instance, a particular enantiomer of a compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

Contemplated equivalents of the compounds described above includecompounds which otherwise correspond thereto, and which have the samegeneral properties thereof (e.g. the ability to inhibit bacterial cellgrowth), wherein one or more simple variations of substituents are madewhich do not adversely affect the efficacy of the compound in inhibitingbacterial cell growth. In general, the compounds of the presentinvention may be prepared by the methods illustrated in the generalreaction schemes as, for example, described below, or by modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants which are in themselves known, but arenot mentioned here.

It will be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described herein above. The permissible substituentscan be one or more and the same or different for appropriate organiccompounds. For purposes of this invention, the heteroatoms such asnitrogen may have hydrogen substituents and/or any permissiblesubstituents of organic compounds described herein which satisfy thevalences of the heteroatoms. This invention is not intended to belimited in any manner by the permissible substituents of organiccompounds.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. Alsofor purposes of this invention, the term “hydrocarbon” is contemplatedto include all permissible compounds having at least one hydrogen andone carbon atom. In a broad aspect, the permissible hydrocarbons includeacyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and nonaromatic organic compounds which can besubstituted or unsubstituted.

The phrase “protecting group” as used herein means temporarysubstituents which protect a potentially reactive functional group fromundesired chemical transformations. Examples of such protecting groupsinclude esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones, respectively. The field ofprotecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York,1991).

The term “ED₅₀” means the dose of a drug which produces 50% of itsmaximum response or effect. Alternatively, the dose which produces apre-determined response in 50% of test subjects or preparations.

The term “LD₅₀” means the dose of a drug which is lethal in 50% of testsubjects.

The term “therapeutic index” refers to the therapeutic index of a drugdefined as LD₅₀/ED₅₀.

The term “structure-activity relationship (SAR)” refers to the way inwhich altering the molecular structure of drugs alters their interactionwith a receptor, enzyme, etc.

The term “agonist” refers to a compound that mimics the action ofnatural transmitter or, when the natural transmitter is not known,causes changes at the receptor complex in the absence of other receptorligands.

The term “antagonist” refers to a compound that binds to a receptorsite, but does not cause any physiological changes unless anotherreceptor ligand is present.

The term “competitive antagonist” refers to a compound that binds to areceptor site; its effects can be overcome by increased concentration ofthe agonist.

The term “partial agonist” refers to a compound that binds to a receptorsite but does not produce the maximal effect regardless of itsconcentration.

The term “ligand” refers to a compound that binds at the receptor site.

II. Compounds of the Invention.

As set out above, the present invention makes available a novel class ofcompounds represented by the general formula 1:

In preferred embodiments, the subject compounds are represented bygeneral formula 1, with the proviso that when X represents N, Yrepresents NH or NCH₃, R₁ is —CO₂H or —CO₂(lower alkyl), R₂ and R₃ eachrepresent H, A and B each represent fused benzo rings, and R₅ is absent,then R₄ does not represent a single chlorine at the 8-position of thequinoline moiety.

In other preferred embodiments, the subject compounds are represented bygeneral formula 1, as generally described above, with the proviso thatwhen X represents N, Y represents NH or NCH₃, R₂ and R₃ each representH, A and B each represent fused benzo rings, R₅ is absent, and R₁comprises an sp²-hybridized carbon at its point of attachment to thearomatic ring containing X, then said sp²-hybridized carbon is itselfbonded, via either single or double bonds, to no more than one oxygenatom.

In a further preferred embodiment, the subject compounds are representedby the general formula 1 as defined above, with the proviso that when Xrepresents N, Y represents NH or NMe, R₂ and R₃ each represent H, and Aand B each independently represent fused benzo rings, then the fusedbenzo ring B is substituted at least once by R₅.

In preferred embodiments of the compounds of general formula 1, theabove general definitions apply, and B is substituted at least once byan R₅.

In preferred embodiments of the compounds of general formula 1, theabove general definitions apply, and at least one of R₂ or R₃ is alkylor aryl.

In preferred embodiments of the compounds of general formula 1, theabove general * definitions apply, except that when R₁ comprises ansp²-hybridized carbon at its point of attachment to the aromatic ringcontaining X; said sp²-hybridized carbon is itself bonded, via eithersingle or double bonds, to no more than one oxygen atom.

Certain of the subject compounds can be classified on the basis ofwhether or not RI comprises a primary or secondary amine functionalgroup. Merely for ease of reading, the application refers to “Class A”compounds, comprising a primary or secondary amine in R₁, and “Class B”compounds, which lack a primary or secondary amine in R₁. The presenceof the amine, as demonstrated in the examples below, can be correlatedwith the potency of the instant compounds against Enterococci.

Class A Compounds

In certain embodiments, the subject compounds are represented by thegeneral formula 1, A, B, X, Y, R, R₂, R₃, R₄, R₅ being defined above,and R₁ representing alkyl(NHR), —C(Z)N(R)(R′—NHR), —C(Z)O(R′—NHR),—S(Z)₂N(R)(R′—NHR), or —P(Z)₂N(R)(R′—NHR), wherein Z independently foreach occurrence represents (R)₂, O, S, or NR, and R′ represents acovalent linker connecting the two nitrogens explicitly depicted abovein the definitions of R₁; R′ preferably being an alkyl, e.g., preferablya cyclic, branched or straight chain aliphatic group of 2-10 bonds inlength, cycloalkyl, alkenyls, cycloalkenyl, alkynyl, aryl, heteroalkyl,or heteroaryl moiety.

In a preferred embodiment, X is N and Y is NR. Where Y represents NR,that occurrence of R is preferably H, alkyl, alkylsulfonyl,arylsulfonyl, or —(CH₂)_(m)—R₈₀, wherein R₈₀ represents an aryl, acycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle, and m is aninteger in the range 0 to 8 inclusive.

In more preferred embodiments, the subject compounds are represented bythe general formula 1, substituents A, B, X, Y, and R being definedabove:

wherein

R₁ represents alkyl(NHR), —C(Z)N(R)(R′—NHR), —C(Z)O(R′—NHR),—S(Z)₂N(R)(R′—NHR), or —P(Z)₂N(R)(R′—NHR), wherein Z independently foreach occurrence represents (R)₂, O, S, or NR;

R′ represents a covalent linker, preferably an alkyl, e.g., morepreferably a cyclic, branched or straight chain aliphatic group of 2-10bonds in length, cycloalkyl, alkenyls, cycloalkenyl, alkynyl, aryl,heteroalkyl, or heteroaryl moiety;

R₂ and R₃, independently for each occurrence, represent H or ahydrophobic aliphatic group, and more preferably R₂ and R₃ represent H,C₁-C₆ alkyl, or aryl, and even more preferably H or —CH₃;

R₄ independently for each occurrence represents C₁-C₆ alkyl, 1-alkenyl,1-alkynyl, aryl, heteroalkyl, heteroaryl, —OR, —OCF₃, —OC(R)₂OR,—C(R)₂OR, or a small hydrophobic moiety (e.g. a halogen or halogenatedalkyl), though preferably R₄ is a halogen, trihalogenated methyl, or—CCR₆₀ (R₆₀ being described below) and more preferably R₄ is a halogen,trihalogenated methyl; and

R₅ independently for each occurrence represents a small hydrophobicmoiety (e.g. preferably a halogen or a halogenated alkyl, such as atrihalogenated methyl such as —CF₃).

In preferred embodiments, when R₁ represents —C(Z)O(R′—NHR), Xrepresents N, Y represents NH or NCH₃, R₂ and R₃ each represent H, A andB each represent fused benzo rings, and R₅ is absent, then R₄ does notrepresent a single chlorine at the 8-position of the quinoline moiety.

In preferred embodiments of the compounds of class A, the above generaldefinitions apply, and B is substituted at least once by R₅.

In preferred embodiments of the compounds of class A, the above generaldefinitions apply, and at least one of R₂ or R₃ is alkyl or aryl.

In preferred embodiments of the compounds of class A, the abovedefinitions apply, and R₁ represents alkyl(NHR), —C(Z)N(R)(R′—NHR),—S(Z)₂N(R)(R′—NHR), or —P(Z)₂N(R)(R′—NHR).

In more preferred embodiments of this class of compounds, the subjectantibacterial compounds are represented by general formula 2:

wherein

R, R_(a), R₃, R₁′, and R₂′, for each occurrence, independently representhydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy,amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl,phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride,silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone,aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal,ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate,epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide,thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀;

R₄, and R₅, for each occurrence, independently represent halogen, alkyl,alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl,alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl,carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl,arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl,nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl,heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(C H₂)_(m)—R₈₀;

T represents a covalent linker, preferably being an alkyl, e.g.,preferably a cyclic, branched or straight chain aliphatic group of 2-10bonds in length, cycloalkyl, alkenyls, cycloalkenyl, alkynyl, aryl,heteroalkyl, or heteroaryl moiety;

the B-rings of the 2-quinolinyl and 3-indolyl moieties may beunsubstituted or substituted between one and four times inclusive by R₄and R₅, respectively;

R₈₀ represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, ora polycycle; and

m is an integer in the range 0 to 8 inclusive.

In preferred embodiments of the compounds of formula 2:

R₂′ and R₃ independently for each occurrence represent H or ahydrophobic aliphatic group, and more preferably R₂′ and R₃ represent H,C₁-C₆ alkyl, or aryl, and even more preferably H or —CH₃;

R₄ independently for each occurrence represents C₁-C₆ alkyl, 1-alkenyl,1-alkynyl, aryl, —OR, —OCF₃, —OC(R)₂OR, —C(R)₂OR, or a small hydrophobicmoiety (e.g. a halogen or halogenated alkyl), preferably R₄ is ahalogen, trihalogenated methyl or —CCR₆₀ (R₆₀ being described below),and more preferably R₄ is a halogen or trihalogenated methyl; and

R₅ independently for each occurrence represents a small hydrophobicmoiety (e.g. a halogen or a halogenated alkyl such as a trihalogenatedmethyl).

In more preferred embodiments of this class of compounds, the subjectantibacterial compounds are represented by the general formula below:

wherein

R, R_(a), R₃, R₅, R₆, R₇, R₈, R₁′, R₂′, R₄′, R₅′, R₆′, and R₇′, for eachoccurrence, independently represent hydrogen, halogen, alkyl, alkenyl,alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl,alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl,carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl,arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl,nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl,heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R₈₀;

T represents a covalent linker, preferably being an alkyl, e.g.,preferably a cyclic, branched or straight chain aliphatic group of 2-10bonds in length, cycloalkyl, alkenyls, cycloalkenyl, alkynyl, aryl,heteroalkyl, or heteroaryl moiety;

R₈₀ represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, ora polycycle; and

m is an integer in the range 0 to 8 inclusive.

In preferred embodiments of the compounds represented above:

R₂′ and R₃ independently for each occurrence represent H or ahydrophobic aliphatic group, and more preferably R₂′ and R₃ represent H,C₁-C₆ alkyl, or aryl, and even more preferably H or —CH₃;

R₅, R₆, R₇, and R₈ independently for each occurrence represent H, C₁-C₆alkyl, 1-alkenyl, 1-alkynyl, aryl, —OR, —OCF₃, —OC(R)₂OR, —C(R)₂OR, or asmall hydrophobic moiety (e.g. a halogen or halogenated alkyl), and morepreferably they are selected from the group comprising halogen,trihalogenated methyl or —CCR₆₀ (R₆₀ being described below); and

R₄′, R₅′, R₆′, and R₇′ represent, independently for each occurrence, H,a small hydrophobic moiety (e.g. a halogen or a halogenated alkyl suchas a trihalogenated methyl).

In more preferred embodiments, the subject antibacterial compounds arerepresented by the following general formula:

wherein

Z represents O or (R)₂;

R, R₃, R₅, R₆, R₇, R₈, R₂₁, R₂₂, R₁′, R₂′, R₄′, R₅′, R₆′, and R₇′, foreach occurrence, independently represent hydrogen, halogen, alkyl,alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl,alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl,carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl,arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl,nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl,heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R₈₀;

R₈₀ represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, ora polycycle; and

m is an integer in the range 0 to 8 inclusive.

In preferred embodiments, Z represents O or (R)₂;

R is as defined above;

R₂′ and R₃, independently for each occurrence, represent H or ahydrophobic aliphatic group, and more preferably R₂′ and R₃ represent H,C₁-C₆ alkyl, or aryl, and even more preferably H or —CH₃;

R₅, R₆, R₇ and R₈ independently for each occurrence represent H, C₁-C₆alkyl, 1-alkenyl, 1-alkynyl, aryl, —OR, —OCF₃, —OC(R)₂OR, —C(R)₂OR, or asmall hydrophobic moiety (e.g. a halogen or halogenated alkyl), and morepreferably R₅, R₆, R₇ and Rx each represent a halogen, trihalogenatedmethyl or —CCR₆₀ (R₆₀ being described below);

R₁′ represents H, alkyl, p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or—(CH₂)_(n)N(R)₂ wherein n is an integer in the range 1 to 6 inclusive;

R₄′, R₅′, R₆′ and R₇′ independently for each occurrence represent H, ora small hydrophobic moiety (e.g. a halogen or a halogenated alkyl, suchas a trihalogenated methyl); and

N(R₂₁)R₂₂ taken together represents a heterocycle comprising from 4 to 8members inclusive; or R₂₁ and R₂₂ independently for each occurrencerepresent H, alkyl, heteroalkyl, aryl, heteroaryl, or —(CH₂)_(m)—R₈₀,though more preferably —(CH₂)_(n)NH(R₁′), wherein n is an integer in therange 1 to 6 inclusive, or ortho-, meta-, or para-CH₂C₆H₄CH₂NH(R₁′), or2-, 3-, or 4-((R₁′)aminomethyl)cyclohexylmethyl, or 2-, 3-, or4-((R₁′)amino)cyclohexyl; with the proviso that R₂, and R₂₂ are selectedsuch that N(R₂₁ )R₂₂ comprises a primary or secondary amine.

The preferred subclass of compounds described above comprises compoundswith minimum inhibitory concentrations (MICs) below 25 μg/mL againstcertain Gram-positive bacteria, especially methicillin-resistantStaphylococcus aureus, ciprofloxacin-resistant Staphylococcus aureus,vancomycin-resistant Enterococcus spp., and/or Streptococcus pneumoniae.Additionally, individual members of the preferred subclass of compoundsdescribed above have MICs below 10 μg/mL, and more preferably MIC valuesless than 7 μg/mL or even less than 1 μg/mL against such bacteria.

Class B Compounds

The absence of a primary or secondary amine in the substituent at the4-position of the quinoline in general structure 2 was tolerated withrespect to maintenance of activity against MRSA and PRP. Other suitablegroups could be selected to increase the polarity and/or stability ofthe resulting compounds. Thus, in yet other embodiments, the subjectcompounds are represented by the general formula 1, A, B, X, Y, R, R₂,R₃, R₄, R₅ being defined in the general formula above, and R₁representing H, Me, lower alkyl, halogen, —C(Z)OR, —C(Z)N(R)₂,—S(Z)₂N(R)₂, or —P(Z)₂N(R)₂, wherein Z independently for each occurrencerepresents (R)₂, O, S, or NR.

In a preferred embodiment, X is N and Y is NR. For those embodimentswherein Y represents NR, that occurrence of R is preferably H, alkyl,alkylsulfonyl, arylsulfonyl, or —(CH₂)m, R₈₀, wherein R₈₀ represents anaryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle, and mis an integer in the range 0 to 8 inclusive.

In certain preferred embodiments, R₁ represents hygrogen or halogen, Xrepresents N, Y represents NH or NCH₃, R₂ and R₃ each independentlyrepresent H, lower alkyl, or aryl, A and B each represent fused benzorings.

In preferred embodiments, when R₁ represents —C(Z)OR, X represents N, Yrepresents NH or NCH₃, R₂ and R₃ each represent H, A and B eachrepresent fused benzo rings, and R₅ is absent, then R₄ does notrepresent a single chlorine at the 8-position of the quinoline moiety.

In preferred embodiments of the compounds of class B, the abovedefinitions apply, and B is substituted at least once by an R₅.

In preferred embodiments of the compounds of class B, the abovedefinitions apply, and at least one of R₂ or R₃ is alkyl or aryl.

In more preferred embodiments, the subject compounds are represented bythe general formula 1, A, B, X, Y, and R being generally defined above:

wherein

R₁ represents H, Me, lower alkyl, halogen, —C(Z)OR, —C(Z)N(R)₂,—S(Z)₂N(R)₂, or —P(Z)₂N(R)₂;

Z independently for each occurrence represents (R)₂, or O;

R₂ and R₃ independently for each occurrence represent H or a hydrophobicaliphatic group, and more preferably R₂ and R₃ represent H, C₁-C₆ alkyl,or aryl, and even more preferably H or —CH₃;

R₄ independently for each occurrence represents C₁-C₆ alkyl, 1-alkenyl,1-alkynyl, aryl, —OR, —OCF₃, —OC(R)₂OR, —C(R)₂OR, or a small hydrophobicmoiety (e.g. a halogen or halogenated alkyl), and more preferably R₄ isa halogen, trihalogenated methyl or —CCR₆₀ (R₆₀ being described below);and

R₅ independently for each occurrence represents a small hydrophobicmoiety (e.g. a halogen or a halogenated alkyl, especially atrihalogenated methyl), —C(O)N(R)₂, —CN, —NO₂, —OH, —OR, —O₂C-aryl, or—O₂C-alkyl.

In further preferred embodiments, the above description applies whereinR₁ represents H, halogen, Me, lower alkyl, —C(Z)N(R)₂, —S(Z)₂N(R)₂, or—P(Z)₂N(R)₂.

In another preferred embodiment, the subject compounds are representedby 1, wherein X represents N; Y represents NH or NMe; R₂ and R₃ eachindependently represent H; A and B each independently represent a fusedbenzo ring; and R₅ is present at least once. In certain preferredembodiments, the subject antibacterial compounds are represented bygeneral formula 3:

wherein

R₃, R₁′, and R₂′, for each occurrence, independently represent hydrogen,halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino,nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate,phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl,alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester,heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide,aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R₈₀;

R₄, and R₅, for each occurrence, independently represent halogen, alkyl,alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl,alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl,carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl,arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl,nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl,heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R₈₀;

the B-rings of the 2-quinolinyl and 3-indolyl moieties may beunsubstituted or substituted between one and four times inclusive by R₄and R₅, respectively;

R₈₀ represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle , ora polycycle; and

m is an integer in the range 0 to 8 inclusive.

In more preferred embodiments of the compounds of formula 3:

R₁′ represents H, alkyl, p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or—(CH₂)_(n)N(R)₂ wherein n is an integer in the range 1 to 6 inclusive;

R₂′ and R₃ independently for each occurrence represent H or ahydrophobic aliphatic group, and more preferably R₂′ and R₃ represent H,C₁-C₆ alkyl, or aryl, and even more preferably H or —CH₃;

R₄ independently for each occurrence represents C₁-C₆ alkyl, 1-alkenyl,1-alkynyl, aryl, —OR, —OCF₃, —OC(R)₂OR, —C(R)₂OR, or a small hydrophobicmoiety (e.g. a halogen or halogenated alkyl), and more preferably R₄represents a halogen, trihalogenated methyl or CCR₆₀ (R₆₀ beingdescribed below); and

R₅ independently for each occurrence represents a small hydrophobicmoiety (e.g. a halogen or a halogenated alkyl, especially atrihalogenated methyl), —C(O)N(R)₂, —CN, —NO₂, —OH, —OR, —O₂Caryl, or—O₂Calkyl.

In more preferred embodiments, the subject antibacterial compounds arerepresented by the following general formula:

wherein

R₁′ represents Hi, alkyl, p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or—(CH₂)_(n)N(R)₂ wherein n is an integer in the range 1 to 6 inclusive;

R₂′ and R₃ independently for each occurrence represent H, C₁-C₆ alkyl,or aryl;

R₅, R₆, R₇, and R₈ independently for each occurrence represent H, C₁-C₆alkyl, 1-alkenyl, 1-alkynyl, aryl, —C(O)N(R)₂, or a small hydrophobicmoiety (e.g. a halogen or halogenated alkyl, preferaby a halogen ortrihalogenated methyl); and

R₄′, R₅′, R₆′ and R₇′ independently for each occurrence represent H, asmall hydrophobic moiety (e.g. a halogen or halogenated alkyl,preferably a halogen or trihalogenated methyl), —C(O)NR₂, —CN, —NO₂,—OH, —OR, —O₂Caryl, or —O₂Calkyl.

The preferred subclass of compounds described above comprises compoundswith minimum inhibitory concentrations (MICs) below 10 μg/mL againstcertain Gram-positive bacteria, especially methicillin-resistantStaphylococcus aureus, ciprofloxacin-resistant Staphylococcus aureus,and/or Streptococcus pneumoniae. In more preferred embodiments, membersof this subclass of compounds have MIC values less than 7 μg/mL or evenless than 1 μg/mL against such bacteria, particularly againstmethicillin-resistant Staphylococcus aureus and/orciprofloxacin-resistant Staphylococcus aureus.

In preferred embodiments, the subject antibacterial compounds arerepresented by general formula 4:

wherein

R₂₀ represents H., Me, lower alkyl, halogen, —C(Z)OR, —C(Z)N(R)₂,—S(Z)₂N(R)₂, or —P(Z)₂N(R)₂, wherein Z independently for each occurrencerepresents (R)₂, O, S, or NR;

R, R₃, R₁′, and R₂′, for each occurrence, independently representhydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy,amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl,phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride,silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone,aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal,ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate,epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide,thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀;

R₄, and R₅, for each occurrence, independently represent halogen, alkyl,alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl,alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl,carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl,arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl,nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl,heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R₈₀;

the B-rings of the 2-quinolinyl and 3-indolyl moieties may beunsubstituted or substituted between one and four times inclusive by R₄and R₅, respectively;

R₈₀ represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, ora polycycle; and

m is an integer in the range 0 to 8 inclusive.

In preferred embodiments of the compounds 4, when R₂₀ represents—C(Z)OR, X represents N, Y represents NH or NCH₃, R₂ and R₃ eachrepresent H, A and B each represent fused benzo rings, and R₅ is absent,then R₄ does not represent a single chlorine at the 8-position of thequinoline moiety.

In preferred embodiments of the subject compounds 4, the above generaldefinitions apply, and R₅ is present at least once.

In preferred embodiments of the subject compounds 4, the above generaldefinitions apply, and at least one of R₂ or R₃ is alkyl or aryl.

In preferred embodiments of the compounds 4, the above definitionsapply, and R₂₀ represents —C(Z)N(R)₂, —S(Z)₂N(R)₂, or —P(Z)₂N(R)₂.

In preferred embodiments of the compounds 4, the above definitionsapply, and R₂₀ represents halogen.

In certain preferred embodiments, the subject antibacterial compoundsare represented by general formula 4, wherein

R₂₀ represents fluorine, chlorine, bromine, or iodine;

R₁′ represents H, alkyl, p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or—(CH₂)_(n)N(R)₂ wherein n is an integer in the range 1 to 6 inclusive;

R₂′ and R₃ independently for each occurrence represent H, Me, C₁-C₆alkyl, or aryl;

the B-rings of the 2-quinolinyl and 3-indolyl moieties may beunsubstituted or substituted between one and four times inclusive by R₄and R₅, respectively;

R₄ independently for each occurrence represents Me, C₁-C₆ alkyl,1-alkenyl, 1-alkynyl, aryl, —OR, —OCF₃, —OCR₂OR, —CR₂OR, or a smallhydrophobic moiety (e.g. a halogen or a halogenated alkyl, preferably atrihalogenated methyl); and

R₅ independently for each occurrence represents a small hydrophobicmoiety (e.g. a halogen or a halogenated alkyl, preferably atrihalogenated methyl), —CN, —NO₂, —OH, —OR, —O₂Caryl, or —O₂Calkyl.

In more preferred embodiments, the above definitions apply, and R₂₀ ischlorine.

More preferably, the subject antibacterial compounds are represented bygeneral formula 4, wherein

R₂₀ represents H, Me, lower alkyl, halogen, —C(Z)OR, —C(Z)N(R)₂,—S(Z)₂N(R)₂, or —P(Z)₂N(R)₂, wherein Z independently for each occurrencerepresents (R)₂, O, S, or NR;

R₁′ represents H, alkyl, p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or—(CH₂)_(n)N(R)₂ wherein n is an integer in the range 1 to 6 inclusive;

R₂′ and R₃ independently for each occurrence represent H, Me, C₁-C₆alkyl, or aryl;

the B-rings of the 2-quinolinyl and 3-indolyl moieties may beunsubstituted or substituted between one and four times inclusive by R₄and R₅, respectively;

R₄ independently for each occurrence represents Me, C₁-C₆ alkyl,1-alkenyl, 1-alkynyl, aryl, —OR, —OCF₃, —OCR₂OR, —CR₂OR, or a smallhydrophobic moiety (e.g. a halogen or a halogenated alkyl, preferably atrihalogenated methyl); and

R₅ independently for each occurrence represents a small hydrophobicmoiety (e.g. a halogen or a halogenated alkyl, preferably atrihalogenated methyl), —CN, —NO₂, —OH, —OR, —O₂Caryl, or —O₂Calkyl.

In preferred embodiments of the subject compounds, the above generaldefinitions apply, and R₅ is present at least once.

In preferred embodiments of the subject compounds, the above generaldefinitions apply, and at least one of R₂ or R₃ is alkyl or aryl.

In still further preferred embodiments, the subject antibacterialcompounds are represented by general formula 4 and the precedingdefinitions, and R₂₀ represents H, Me, lower alkyl, halogen, —C(Z)N(R)₂,—S(Z)₂N(R)₂, or —P(Z)₂N(R)₂, wherein Z independently for each occurrencerepresents (R)₂, O, S, or NR.

In further preferred embodiments, the above descriptions based on 4apply wherein R₂₀ represents H, Me, lower alkyl, halogen, —C(Z)OR,—C(Z)N(R)₂, —S(Z)₂N(R)₂, or —P(Z)₂N(R)₂, wherein Z independently foreach occurrence represents (R)₂, O, S, or NR; and R₅ is present at leastonce.

In additional preferred embodiments, the subject antibacterial compoundsare represented by the following general formula:

wherein

Z represents O or (R)₂;

R₂′ and R₃ independently for each occurrence represent H or ahydrophobic aliphatic group, and more preferably R₂′ and R₃ represent H,C₁-C₆ alkyl, or aryl, and even more preferably H or —CH₃;

R₅, R₆, R₇ and R₈ independently for each occurrence represent H, C₁-C₆alkyl, 1-alkenyl, 1-alkynyl, aryl, —OR, —OCF₃, —OC(R)₂OR, —C(R)₂OR, or asmall hydrophobic moiety (e.g. a halogen or halogenated alkyl), and morepreferably R₅, R₆, R₇ and R₈ represent H, halogen, trihalogenatedmethyl, or —CCR₆₀ (R₆₀ being described below);

R₁′ represents H, alkyl, aryl, p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or—(CH₂)_(n)N(R)₂ wherein n is an integer in the range 1 to 6 inclusive;

R₄′, R₅′, R₆′ and R₇′ independently for each occurrence represent H, ora small hydrophobic moiety (e.g. a halogen or a halogenated alkyl,especially a trihalogenated methyl); and

R₂₁ and R₂₂ independently for each occurrence represent H, alkyl,heteroalkyl, aryl, heteroaryl, ortho-, meta-, orpara-CH₂C₆H₄O(R₁′),ortho-, meta-, orpara-CH₂C₆H₄OMe, ortho-, meta-, or para-CH₂C₆H₄OH,(2-benzimidazolyl)CH₂—, 2-, 3-, or 4-methoxyphenyl, 2-, 3-, or4-hydroxyphenyl, or 2-, 3-, or 4-((R₁′)₂NCH₂)cyclohexylmethyl, or 2-,3-, or 4-((R₁′)₂N)cyclohexyl; or N(R₂₁ )R₂₂ taken together represents aheterocycle comprising from 4 to 8 members inclusive; with the provisothat, regardless of the specific identity of N(R₂₁)R₂₂, it does notinclude a primary or secondary amine.

The preferred subclass of compounds described above comprises compoundswith minimum inhibitory concentrations (MICS) below 10 μg/mL againstcertain Gram-positive bacteria, especially methicillin-resistantStaphylococcus aureus, ciprofloxacin-resistant Staphylococcus aureus,and/or Streptococcus pneumoniae. Additionally, individual members of thepreferred subclass of compounds described above have MICs less than 7μg/mL or even less than 1 μg/mL against such bacteria.

Alkynyl-substituted

In still other embodiments, the subject antibacterial compounds arerepresented by the following general formula:

wherein

R₃, R₄, R₁′, R₂′, and R₆₀ for each occurrence, independently representhydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy,amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl,phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride,silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone,aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal,ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate,epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide,thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀;

R₅, and R₇, for each occurrence, independently represent halogen, alkyl,alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl,alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl,carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl,arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl,nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl,heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R₈₀;

the B-ring of the 2-quinolinyl moiety may be unsubstituted beyond thealkynyl group or substituted between one and three times inclusive byR₅;

the B-ring of the 3-indolyl moiety may be unsubstituted or substitutedbetween one and four times inclusive by R₇;

R₈₀ represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle , ora polycycle; and

m is an integer in the range 0 to 8 inclusive.

In preferred embodiments, R₆₀ represents alkyl, alkenyl, alkynyl,hydroxyl, alkoxyl, or —C(Z)—R₆; where R₆ is selected from the groupcomprising NHR, N(R)₂, 1-piperidyl, 1-piperazinyl, 1-pyrrolidinyl,2-phenylethylamino, 4-morpholinyl, and 4-phenylmethyl-1-piperidyl; Zindependently for each occurrence represents (R)₂, O, S, or NR; and R isH or a lower alkyl.

In more preferred embodiments, the subject antibacterial compounds arerepresented by the following general formula:

wherein

Z independently for each occurrence represents (R)₂, O, S, or NR;

R₅, R₇, and R₈ independently for each occurrence represent H, Me, C₁-C₆alkyl, heteroalkyl, 1-alkenyl, 1-alkynyl, aryl, heteroaryl, —OR, —OCF₃,—OCR₂OR, —CR₂OR, —CO₂R, or a small hydrophobic moiety (e.g. a halogen ora halogenated alkyl, preferably a trihalogenated methyl);

R₆ is selected from the group comprising NHR, N(R)₂, 1-piperidyl,1-piperazinyl, 1-pyrrolidinyl, 2-phenylethylamino, 4-morpholinyl, and4-phenylmethyl-1-piperidyl;

R₁′ represents H, alkyl, aryl, p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or—(CH₂)_(n)N(R)₂; wherein n is an integer in the range 1 to 6 inclusive;

R₂′ and R₃ independently for each occurrence represent H, Me, C₁-C₆alkyl, or aryl;

R₄′, R₅′, R₆′ and R₇′ independently for each occurrence represent H, asmall hydrophobic moiety (e.g. a halogen or a halogenated alkyl,preferably a trihalogenated methyl), —C(O)NR₂, —N, —NO₂, —OH, —OR,—O₂Caryl, or —O₂Calkyl; and

R₂₁ and R₂₂ independently for each occurrence represent H, alkyl,heteroalkyl, aryl, —heteroaryl, —(CH₂)_(m)—R₈₀, and more preferably—(CH₂)_(n)N(R₁′)₂, wherein n is an integer in the range 1 to 6inclusive, ortho-, meta-, or para-CH₂C₆H₄CH₂N(R₁′)₂, ortho-, meta-, orpara-C₆H₄CH₂N(R₁′)₂, ortho-, meta-, orpara-CH₂C₆H₄O(R₁′), ortho-, meta-,orpara-CH₂C₆H₄OMe, ortho-, meta-, orpara-CH₂C₆H₄OH,(2-benzimidazolyl)CH₂—, 2-, 3-, or 4-(R₁′)Ophenyl, 2-, 3-, or4-methoxyphenyl, 2-, 3-, or 4-hydroxyphenyl, or 2-, 3-, or4-((R₁′)₂NCH₂)cyclohexylmethyl, or 2-, 3-, or4-((R₁′)₂N)cyclohexylmethyl; or N(R₂₁)R₂₂ taken together represent aheterocycle comprising from 4 to 8 members inclusive.

In additional preferred embodiments, the subject antibacterial compoundsare represented by the following general formula:

wherein

Z independently for each occurrence represents (R)₂, O, S, or NR;

R₅, R₇, and R₈ independently for each occurrence represent H, Me, C₁-C₆alkyl, heteroalkyl, 1-alkenyl, 1-alkynyl, aryl, heteroaryl, —OR, —OCF₃,—OCR₂OR, —CR₂OR, —CO₂R, or a small hydrophobic moiety (e.g. a halogen ora halogenated alkyl, preferably a trihalogenated methyl);

R₆ is selected from the group comprising NHR, N(R)₂, 1-piperidyl,1-piperazinyl, 1-pyrrolidinyl, 2-phenylethylamino, 4-morpholinyl, and4-phenylmethyl-1-piperidyl;

R₁′ represents H, alkyl, aryl, p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or—(CH₂)_(n)N(R)₂ wherein n is an integer in the range 1 to 6 inclusive;

R₂′ and R₃ independently for each occurrence represent H, Me, C₁-C₆alkyl, or aryl;

R₄′, R₅′, R₆′ and R₇′ independently for each occurrence represent H, asmall hydrophobic moiety (e.g. a halogen or a halogenated alkyl,preferably a trihalogenated methyl), —C(O)NR₂, —CN, —NO₂, —OH, —OR,—O₂Caryl, or —O₂Calkyl; and

m and n are integers independently selected from the range 1 to 4inclusive.

The preferred subclasses of compounds described above comprisescompounds with minimum inhibitory concentrations (MICs) below 10 μg/mLagainst certain Gram-positive bacteria, especially methicillin-resistantStaphylococcus aureus, ciprofloxacin-resistant Staphylococcus aureus,vancomycin-resistant Enterococcus spp., or Streptococcus pneumoniae.Additionally, members of this subclass of compounds have MIC values lessthan 7 μg/mL or even less than 1 μg/mL against such bacteria,particularly against methicillin- and/or ciprofloxacin-resistantStaphylococcus aureus.

In more preferred embodiments, the subject antibacterial compounds arerepresented by the following general formula:

wherein

Z independently for each occurrence represents (R)₂, O, S, or NR;

R₅, R₆, and R₈ independently for each occurrence represent H, Me, C₁-C₆alkyl, heteroalkyl, 1-alkenyl, 1-alkynyl, aryl, heteroaryl, —OR, —OCF₃,—OCR₂OR, —CR₂OR, —CO₂R, or a small hydrophobic moiety (e.g. a halogen ora halogenated alkyl, preferably a trihalogenated methyl);

R₇ is selected from the group comprising NHR, N(R)₂, 1-piperidyl,1-piperazinyl, 1-pyrrolidinyl, 2-phenylethylamino, 4-morpholinyl, and4-phenylmethyl-1-piperidyl;

R₁′ represents H, alkyl, aryl, p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or—(CH₂)_(n)N(R)₂; wherein n is an integer in the range 1 to 6 inclusive;

R₂′ and R₃ independently for each occurrence represent H, Me, C₁-C₆alkyl, or aryl;

R₄′, R₅′, R₆′ and R₇′ independently for each occurrence represent H, asmall hydrophobic moiety (e.g. a halogen or a halogenated alkyl,preferably a trihalogenated methyl), —C(O)NR₂, —CN, —NO₂, —OH, —OR,—O₂Caryl, or —O₂Calkyl; and

R₂₁ and R₂₂ independently for each occurrence represent H, alkyl,heteroalkyl, aryl, heteroaryl, —(CH₂)_(m)—R₈₀, and more preferably—(CH₂)_(n)N(R₁′)₂, wherein n is an integer in the range 1 to 6inclusive, ortho-, meta-, or para-CH₂C₆H₄CH₂N(R₁′)₂, ortho-, meta-, orpara-C₆H₄CH₂N(R₁′)₂, ortho-, meta-, or para-CH₂C₆H₄O(R₁′), ortho-,meta-, or para-CH₂C₆H₄OMe, ortho-, meta-, orpara-CH₂C₆H₄OH,(2-benzimidazolyl)CH₂—, 2-, 3-, or 4-(R₁′)Ophenyl, 2-, 3-, or4-methoxyphenyl, 2-, 3-, or 4-hydroxyphenyl, or 2-, 3-, or4-((R₁′)₂NCH₂)cyclohexylmethyl, or 2-, 3-, or4-((R₁′)₂N)cyclohexylmethyl; or N(R₂₁)R₂₂ taken together represent aheterocycle comprising from 4 to 8 members inclusive.

In additional preferred embodiments, the subject antibacterial compoundsare represented by the following general formula:

wherein

Z independently for each occurrence represents (R)₂, O, S, or NR;

R₅, R₆, and R₈ independently for each occurrence represent H, Me, C₁-C₆alkyl, heteroalkyl, 1-alkenyl, 1-alkynyl, aryl, heteroaryl, —OR, —OCF₃,—OCR₂OR, —CR₂OR, —CO₂R, or a small hydrophobic moiety (e.g. a halogen ora halogenated alkyl, preferably a trihalogenated methyl);

R₇ is selected from the group comprising NHR, N(R)₂, 1-piperidyl,1-piperazinyl, 1- pyrrolidinyl, 2-phenylethylamino, 4-morpholinyl, and4-phenylmethyl-1-piperidyl;

R₁′ represents H, alkyl, aryl, p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or—(CH₂)_(n)N(R)₂ wherein n is an integer in the range 1 to 6 inclusive;

R₂′ and R₃ independently for each occurrence represent H, Me, C₁-C₆alkyl, or aryl;

R₄′, R₅′, R₆′ and R₇′ independently for each occurrence represent H, asmall hydrophobic moiety (e.g. a halogen or a halogenated alkyl,preferably a trihalogenated methyl), —C(O)NR₂, —CN, —NO₂, —OH, —OR,—O₂Caryl, or —O₂Calkyl; and

m and n are integers independently selected from the range 1 to 4inclusive.

In further preferred embodiments, the subject antibacterial compoundsare represented by the following general formula:

wherein

Z independently for each occurrence represents (R)₂, O, S, or NR;

R₅, R₆, and R₇ independently for each occurrence represent H, Me, C₁-C₆alkyl, heteroalkyl, 1-alkenyl, 1-alkynyl, aryl, heteroaryl, —OR, —OCF₃,—OCR₂OR, —CR₂OR, —CO₂R, or a small hydrophobic moiety (e.g. a halogen ora halogenated alkyl, preferably a trihalogenated methyl);

R₈ is selected from the group comprising NHR, N(R)₂, 1-piperidyl,1-piperazinyl, 1-pyrrolidinyl, 2-phenylethylamino, 4-morpholinyl, and4-phenylmethyl-1-piperidyl;

R₁′ represents H, alkyl, aryl, p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or—(CH₂)_(n)N(R)₂ wherein n is an integer in the range 1 to 6 inclusive;

R₂′ and R₃ independently for each occurrence represent H, Me, C₁-C₆alkyl, or aryl;

R₄′, R₅′, R₆′ and R₇′ independently for each occurrence represent H, asmall hydrophobic moiety (e.g. a halogen or a halogenated alkyl,preferably a trihalogenated methyl), —C(O)NR₂, —CN, —NO₂, —OH, —OR,—O₂Caryl, or —O₂Calkyl; and

R₂₁ and R₂₂ independently for each occurrence represent H, alkyl,heteroalkyl, aryl, heteroaryl, —(CH₂)_(m)—R₈₀, and more preferably—(CH₂)_(n)N(R₁′)₂, wherein n is an integer in the range 1 to 6inclusive, ortho-, meta-, or para-CH₂C₆H₄CH₂N(R₁′)₂, ortho-, meta-, orpara-C₆H₄CH₂N(R₁′)₂, ortho-, meta-, or para-CH₂C₆H₄O(R₁′), ortho-,meta-, or para-CH₂C₆H₄OMe, ortho-, meta-, orpara-CH₂C₆H₄OH,(2-benzimidazolyl)CH₂—, 2-, 3-, or 4-(R₁′)Ophenyl, 2-, 3-, or4-methoxyphenyl, 2-, 3-, or 4-hydroxyphenyl, or 2-, 3-, or4-((R₁′)₂NCH₂)cyclohexylmethyl, or 2-, 3-, or4-((R₁′)₂N)cyclohexylmethyl; or N(R₂,)R₂₂ taken together represent aheterocycle comprising from 4 to 8 members inclusive.

In additional preferred embodiments, the subject antibacterial compoundsare represented by the following general formula:

wherein

Z independently for each occurrence represents (R)₂, O, S, or NR;

R₅, R₆, and R₇ independently for each occurrence represent H, Me, C₁-C₆alkyl, heteroalkyl, 1-alkenyl, 1-alkynyl, aryl, heteroaryl, —OR, —OCF₃,—OCR₂OR, —CR₂OR, —CO₂R, or a small hydrophobic moiety (e.g. a halogen ora halogenated alkyl, preferably a trihalogenated methyl);

R₈ is selected from the group comprising NHR, N(R)₂, 1-piperidyl,1-piperazinyl, 1-pyrrolidinyl, 2-phenylethylamino, 4-morpholinyl, and4-phenylmethyl-1-piperidyl;

R₁′ represents H, alkyl, aryl,p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or—(CH₂)_(n)N(R)₂ wherein n is an integer in the range 1 to 6 inclusive;

R₂′ and R₃ independently for each occurrence represent H, Me, C₁-C₆alkyl, or aryl;

R₄′, R₅′, R₆′ and R₇′ independently for each occurrence represent H, asmall hydrophobic moiety (e.g. a halogen or a halogenated alkyl,preferably a trihalogenated methyl), —C(O)NR₂, —CN, —NO₂, —OH, —OR,—O₂Caryl, or —O₂Calkyl; and

m and n are integers independently selected from the range 1 to 4inclusive.

The antibacterial properties of the compounds of the present inventionmay be determined from a bacterial lysis assay, as well as by othermethods, including, inter alia, growth inhibition assays (e.g., such asdescribed by Blondelie et al. (1992) Biochemistry 31:12688),fluorescence-based bacterial viability assays (e.g., Molecular ProbesBacLight), flow cytometry analyses (Arroyo et al. (1995) J. Virol. 69:4095-4102), and other standard assays known to those skilled in the art.

The assays for growth inhibition of a microbial target can be used toderive an ED₅₀ value for the compound, that is, the concentration ofcompound required to kill 50% of the microbial sample being tested.

Alternatively, growth inhibition by an antimicrobial compound of theinvention may also be characterized in terms of the minimum inhibitoryconcentration (MIC), which is the concentration of compound required toachieve inhibition of microbial cell growth. Such values are well knownto those in the art as representative of the effectiveness of aparticular antimicrobial agent (e.g., an antibiotic) against aparticular organism or group of organisms. For instance, cytolysis of abacterial population by an antimicrobial compound can also becharacterized, as described above by the minimum inhibitoryconcentration, which is the concentration required to reduce the viablebacterial population by 99.9%. The value of MIC₅₀ can also be used,defined as the concentration of a compound required to reduce the viablebacterial population by 50%. In preferred embodiments, the compounds ofthe present invention are selected for use based, inter alia, on havingMIC values of less than 25 μg/mL, more preferably less than 7 μg/mL, andeven more preferably less than 1 μg/mL against a desired bacterialtarget, e.g., a Gram positive bacteria such as methicillin-resistantStaphylococcus aureus, ciprofloxacin-resistant Staphylococcus aureus, orStreptococcus pneumoniae.

Another parameter useful in identifying and measuring the effectivenessof the antimicrobial compounds of the invention is the determination ofthe kinetics of the antimicrobial activity of a compound. Such adetermination can be made by determining antimicrobial activity as afunction of time. In a preferred embodiment, the compounds displaykinetics which result in efficient lysis of a microorganism. In apreferred embodiment, the compounds are bacteriocidal.

Furthermore, the preferred antimicrobial compounds of the inventiondisplay selective toxicity to target microorganisms and minimal toxicityto mammalian cells. Determination of the toxic dose (or “LD₅₀”) can becarried using protocols well known in the field of pharmacology.Ascertaining the effect of a compound of the invention on mammaliancells is preferably performed using tissue culture assays, e.g., thepresent compounds can be evaluated according to standard methods knownto those skilled in that art (see for example Gootz, T. D. (1990) Clin.Microbiol. Rev. 3:13-31). For mammalian cells, such assay methodsinclude, inter alia, trypan blue exclusion and MTT assays (Moore et al.(1994) Compound Research 7:265-269). Where a specific cell type mayrelease a specific metabolite upon changes in membrane permeability,that specific metabolite may be assayed, e.g., the release of hemoglobinupon the lysis of red blood cells (Srinivas et al. (1992) J. Biol. Chem.267:7121-7127). The compounds of the invention are preferably testedagainst primary cells, e.g., using human skin fibroblasts (HSF) or fetalequine kidney (FEK) cell cultures, or other primary cell culturesroutinely used by those skilled in the art. Permanent cell lines mayalso be used, e.g., Jurkat cells. In preferred embodiments, the subjectcompounds are selected for use in animals, or animal cell/tissue culturebased at least in part on having LD₅₀'s at least one order of magnitudegreater than the MIC or ED₅₀ as the case may be, and even morepreferably at least two, three and even four orders of magnitudegreater. That is, in preferred embodiments where the subject compoundsare to be administered to an animal, a suitable therapeutic index ispreferably greater than 10, and more preferably greater than 10, 1000 oreven 10,000.

Antibacterial assays for the compounds of the invention can be performedto determine the bacterial activity toward both Gram-positive andGram-negative microorganisms. Typical Gram-negative pathogens which maybe sensitive to the antibacterial agents of the present invention caninclude, for example, species of genus Escherichia, genus Enterobacter,genus Klebsiella, genus Serratia, genus Proteus and genus Pseudomonas.For example, the subject compositions and methods can be used as part oftreatment and prevention regimens for infections by some of the mostfrequently encountered Gram-negative and Gram-positive organisms,including those involving Escherichia coli (E. coli), Klebsiellapeumoniae (K. peumoniae), Serratia marcescens, Enterobacter aerogenesand Enterobacter cloacae (E. aerogenes and E. cloacae), Pseudomonasaeruginosa (P. aeruginosa), Neisseria meningitidis (N. meningitidis),Group B Streptococcus aureus and Staphylococcus aureus, Streptococcuspneumonia, Streptococcus pyogenes, Corynebacter diphtheriae,Gardnierella vaginalis, Actinetobacter spp., Bordella pertussis,Haemophilus aegyptius, Haemophilus influenza, Haemophilus ducreyi,Shigella spp, Serratia spp., and Propionibacterium acnes.

The above list of pathogens is purely illustrative and is in no way tobe interpreted as restrictive.

Examples of conditions which can be treated include illnesses of therespiratory passages and of the pharyngeal cavity; otitis, pharyngitis,pneumonia, peritonitis, pyelonephritis, cystitus, endocarditis, systemicinfections, bronchitis, arthritis, local inflammations, skin infections,conjuntivitus, and infections of any surgically created vascular accessfor the purpose of hemodialysis.

The antibiotics of the present invention can also be usedprophylactically in animal breeding and livestock husbandry, and as anagents for promoting and accelerating growth and for improving feedstuffutilization in both healthy and sick animals.

In preferred embodiments, the antibacterial agents of the presentinvention are selected based on their ability to inhibit growth ofGram-positive bacteria. Such Gram-positive bacteria include bacteriafrom the following species: Staphylococcus, Streptococcus, Micrococcus,Peptococcus, Peptostreptococcus, Enterococcus, Bacillus, Clostridium,Lactobacillus, Listeria, Erysipelothrix, Propionibacterium, Eubacterium,and Corynebacterium.

A variety of Gram-positive organisms are capable of causing sepsis. Themost common organisms involved in sepsis are Staphylococcus aureus,Streptoccocus pneumoniae, coagulase-negative staphylococci,beta-hemolytic streptococci, and enterococci, but any Gram-positiveorganism may be involved. (see, e.g., Bone, (1993) J. Critical Care8:51-59). Thus, it is specifically contemplated that the subjectcompositions and methods can be used as part of a therapeutic treatmentor prevention program for sepsis involving Gram-positive bacteria.

Accordingly, in one embodiment, S. aureus is used as a model of aGram-positive microorganism in testing/selecting the compounds of thepresent invention. This bacteria is also a significant clinical targetas well because it is refractive to most systemic antibiotic treatments.Staphylococcus aureus is the most frequent cause of skin, wound, andblood infections and the second most frequent cause of lower respiratorytract infections, and the microorganism tends to prey onimmunocompromised and institutionalized patients. Thus, the subjectcompounds can be used to treat such infections caused by Staphylococcus,as well as in the treatment of conjunctivitis, outer ear infections andthe like.

One of the key contributors to the increase in mortality and morbiditydue to bacterial infections is the increasing prevalence ofdrug-resistant bacteria. Examples of the seriousness of antibioticresistance are methicillin-resistant S. aureus (MRSA),ciprofloxacin-resistant S. aureus (CRSA), and the emergence ofvancomycin-resistant S. aureus which have become resistant to virtuallyall currently used antibiotics. Thus, methicillin-resistant S. aureusmay also be used as an antibiotic-resistant model organism for selectingthe subject compounds. In a preferred embodiment, the antibacterialagents of the present invention can be used in the treatment and/orprevention of endocarditis, e.g., which may be caused by MRSA or CRSA.

The heavy use of vancomycin to treat MRSA infections has in turncontributed to the emergence of new strains of enterococci, the thirdmost prevalent cause of bacterial infection in the U.S., which areresistant to vancomycin. Enterococcus causes as many as 15 percent ofbacterial endocarditis cases; it is also the cause of meningitis, andinfections in the urinary tract, stomach and intestines. Infectionscaused by these vancomycin-resistant enterococci (VRE) frequently do notrespond to any current therapies, and in many cases prove fatal.Accordingly, the subject compounds can be selected using an assay basedon E. faecalis sensitivity, and in particular, the vancomycin-resistantisolates found in clinical settings such as a hospital.

The subject compositions may also be selected for treatment of infectionby Streptococcus. Streptococcus species are found associated in a greatvariety of pathologic conditions among which are gangrene, puerperalinfections, subacute bacterial endocarditis, septic sore throat,rheumatic fever, and pneumonia. Agents which are active againstStreptococcus species are, therefore, greatly needed.

To further illustrate, E. coli and P. aeruginosa are examples ofGram-negative organisms which may be sensitive to the subjectantibacterial agents. P. aeruginosa is a particularly problematic sourceof disease in such conditions as lung infections in patients with cysticfibrosis, burn infections, eye and urinary tract infections, andinfection with P. aeruginosa may result in serious septicemia. Moreover,imipenem-resistant P. aeruginosa are increasing in the clinical field.Enteropathogenic E. coli are responsible for outbreaks of diarrhea ininfants and newborns, and diarrhea, including “traveler's diarrhea”, inadults. E. coli may be invasive and toxin-producing, causing sometimesfatal infections, such as cystitis, pyelitis, pyelonephritis,appendicitis, peritonitis, gallbladder infection, septicemia, meningitisand endocarditis.

In still other embodiments, the subject compounds can be used in thetreatment of infections caused by Serratia spp. For instance, S.marcescens is a source of ophthalmic and other topical infections, andcan be readily provided in assays intended to identify those compoundsof the present invention which are bactercidal at suitableconcentrations against that bacteria.

The subject compounds may also be used in the treatment of external earinfections (otitis externa), or in the treatment of sexually transmitteddiseases such as Niesseria gonorrhea and trichomonas infections.

Certain compounds according to the invention may also be selected on thebasis of their activity against typical and atypical Mycobacteria andHelicobacter pylori, and also against bacteria-like microorganisms, suchas, for example, Mycoplasma and Rickettsia. They are thereforeparticularly suitable in human and veterinary medicine for theprophylaxis and chemotherapy of local and systemic infections caused bythese pathogens. Mycobacterium boris, like M. tuberculosis, M.africanum, M. ulcerans, and M. leprae, is a strict pathogen. M bovis isa significant pathogen throughout much of the world, causingtuberculosis, primarily in cattle.

In other embodiments, the subject compositions can be used in thetreatment/prevention of infection by Salmonella. Salmonella spp. causefood poisoning, resulting in nausea, vomiting, diarrhea andsometimes-fatal septicemia. For instance, S. typhi is the etiologicalagent of typhoid fever.

The compositions and methods of the present invention may also be usefulin the treatment of infection by Shigella. Shigella spp., including S.dysenteriae, are common waterborne pathogenic agents, causing bacillarydysentery as well as bacteremia and pneumonia.

In the United States and Canada, S. sonnei and S. flexneri have becomethe most common etiological agents in bacillary dysentery.

Bacteria of the genus Yersinia are also pathogens which may be treatedby the subject compositions. Y. Enterocolitica, for example, is anenteric pathogen. Infection with this microorganism causes severediarrhea, gastroenteritis and other types of infections such asbacteremia, peritonitis, cholecystis, visceral abscesses, and mesentericlymphadenitis.

Septicemia with 50% mortality has been reported. Y. pestis is theetiologic agent of bubonic, pneumonic, and septicemic plague in humans.

The subject compositions can be used for sterilization of surfaces suchas countertops, surgical instruments, bandages, and skin; aspharmaceutical compositions, including by way of example creams,lotions, ointments, or solutions for external application to skin andmucosal surfaces, including the cornea, dernial cuts and abrasions,bums, and sites of bacterial or fungal infection; as pharmaceuticalcompositions, including by way of example creams, lotions, ointments,emulsions, liposome dispersions, tablets, or solutions, foradministration to internal mucosal surfaces such as the oral cavity orvagina to inhibit the growth of bacteria (or other microorganisms); andas pharmaceutical compositions such as creams, gels, or ointments forcoating indwelling invasive devices such as intravenous lines andcatheters and similar implants which are susceptible to harboringbacteria.

The subject compositions are also useful for sterilization of in vitrotissue and cell culture media.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given by formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc. administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral and topical administrations are preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms such as described below orby other conventional methods known to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide prodrugs thereof, theroute of administration, the time of administration, the rate ofexcretion of the particular compound being employed, the duration of thetreatment, other drugs, compounds and/or materials used in combinationwith the particular antibacterial employed, the age, sex, weight,condition, general health and prior medical history of the patient beingtreated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Generally, intravenous,intracerebroventricular, subcutaneous, and topical doses of thecompounds of this invention for a patient, when used for the indicatedantibacterial effects, will range from about 0.0001 to about 100 mg perkilogram of body weight per day.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

The term “treatment” is intended to encompass also prophylaxis, therapyand cure.

The patient receiving this treatment is any animal in need, includingprimates, and in particular humans, and other mammals such as equines,cattle, swine and sheep; and poultry and pets in general.

The compound of the invention can be administered as such or inadmixtures with pharmaceutically acceptable carriers and can also beadministered in conjunction with other antimicrobial agents such aspenicillins, cephalosporins, aminoglycosides and glycopeptides.Conjunctive therapy, thus includes sequential, simultaneous and separateadministration of the active compound in a way that the therapeuticaleffects of the first administered compound has not entirely disappearedwhen the subsequent compound is administered.

III. Pharmaceutical Compositions

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical formulation (composition). The antibiotic compoundsaccording to the invention may be formulated for administration in anyconvenient way for use in human or veterinary medicine, by analogy withother antibiotics.

Thus, another aspect of the present invention provides pharmaceuticallyacceptable compositions comprising a therapeutically-effective amount ofone or more of the compounds described above, formulated together withone or more pharmaceutically acceptable carriers (additives) and/ordiluents. As described in detail below, the pharmaceutical compositionsof the present invention may be specially formulated for administrationin solid or liquid form, including those adapted for the following: (1)oral administration, for example, drenches (aqueous or non-aqueoussolutions or suspensions), tablets, boluses, powders, granules, pastesfor application to the tongue; (2) parenteral administration, forexample, by subcutaneous, intramuscular or intravenous injection as, forexample, a sterile solution or suspension; (3) topical application, forexample, as a cream, ointment or spray applied to the skin; or (4)intravaginally or intrarectally, for example, as a pessary, cream orfoam. However, in certain embodiments the subject compounds may besimply dissolved or suspended in sterile water.

The phrase “therapeutically-effective amount” as used herein means thatamount of a compound, material, or composition comprising a compound ofthe present invention which is effective for producing some desiredtherapeutic effect by inhibiting bacterial cell growth when administeredto an animal, at a reasonable benefit/risk ratio applicable to anymedical treatment.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically-acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting the subject antibacterialagent from one organ, or portion of the body, to another organ, orportion of the body. Each carrier must be “acceptable” in the sense ofbeing compatible with the other ingredients of the formulation and notinjurious to the patient. Some examples of materials which can serve aspharmaceutically-acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

As set out above, certain embodiments of the present antibacterials maycontain a basic functional group, such as amino or alkylamino, and are,thus, capable of forming pharmaceutically-acceptable salts withpharmaceutically-acceptable acids. The term “pharmaceutically-acceptablesalts” in this respect, refers to the relatively non-toxic, inorganicand organic acid addition salts of compounds of the present invention.These salts can be prepared in situ during the final isolation andpurification of the compounds of the invention, or by separatelyreacting a purified compound of the invention in its free base form witha suitable organic or inorganic acid, and isolating the salt thusformed. Representative salts include the hydrobromide, hydrochloride,sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate,palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate,glucoheptonate, lactobionate, and laurylsulphonate salts and the like.(See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm.Sci. 66:1-19)

The pharmaceutically acceptable salts of the subject compounds includethe conventional nontoxic salts or quaternary ammonium salts of thecompounds, e.g., from non-toxic organic or inorganic acids. For example,such conventional nontoxic salts include those derived from inorganicacids such as hydrochloride, hydrobromic, sulfuric, sulfamic,phosphoric, nitric, and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicyclic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isothionic, and the like.

In other cases, the compounds of the present invention may contain oneor more acidic functional groups and, thus, are capable of formingpharmaceutically-acceptable salts with pharmaceutically-acceptablebases. The term “pharmaceutically-acceptable salts” in these instancesrefers to the relatively non-toxic, inorganic and organic base additionsalts of compounds of the present invention. These salts can likewise beprepared in situ during the final isolation and purification of thecompounds, or by separately reacting the purified compound in its freeacid form with a suitable base, such as the hydroxide, carbonate orbicarbonate of a pharmaceutically-acceptable metal cation, with ammonia,or with a pharmaceutically-acceptable organic primary, secondary ortertiary amine. Representative alkali or alkaline earth salts includethe lithium, sodium, potassium, calcium, magnesium, and aluminum saltsand the like. Representative organic amines useful for the formation ofbase addition salts include ethylamine, diethylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine and the like. (See, forexample, Berge et al., supra).

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate, magnesium stearate, and polyethylene oxide-polypropylene oxidecopolymer as well as coloring agents, release agents, coating agents,sweetening, flavoring and perfuming agents, preservatives andantioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect.Generally, out of one hundred per cent, this amount will range fromabout 1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient is mixed with one or more pharmaceutically-acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: (1) fillers or extenders, such as starches, lactose,sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as,for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol;(4) disintegrating agents, such as agar—agar, calcium carbonate, potatoor tapioca starch, alginic acid, certain silicates, sodium carbonate,and sodium starch glycolate; (5) solution retarding agents, such asparaffin; (6) absorption accelerators, such as quaternary ammoniumcompounds; (7) wetting agents, such as, for example, cetyl alcohol,glycerol monostearate, and polyethylene oxide-polypropylene oxidecopolymer; (8) absorbents, such as kaolin and bentonite clay; (9)lubricants, such a talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and(10) coloring agents. In the case of capsules, tablets and pills, thepharmaceutical compositions may also comprise buffering agents. Solidcompositions of a similar type may also be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugars, as well as high molecular weight polyethylene glycols andthe like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containopacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof. Additionally, cyclodextrins,e.g. hydroxypropyl-β-cyclodextrin, may be used to solubilize compounds.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar—agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active antibacterial.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the antibacterial in theproper medium. Absorption enhancers can also be used to increase theflux of the antibacterial across the skin. The rate of such flux can becontrolled by either providing a rate controlling membrane or dispersingthe compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacteriostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants. Because solutions are particularly important forintravenous administration, solubilizing agents, e.g. cyclodextrins, canbe used.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents which delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. One strategy for depot injections includes the use ofpolyethylene oxide-polypropylene oxide copolymers wherein the vehicle isfluid at room temperature and solidifies at body temperature.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99.5% (morepreferably, 0.5 to 90%) of active ingredient in combination with apharmaceutically acceptable carrier.

The addition of the active compound of the invention to animal feed ispreferably accomplished by preparing an appropriate feed premixcontaining the active compound in an effective amount and incorporatingthe premix into the complete ration.

Alternatively, an intermediate concentrate or feed supplement containingthe active ingredient can be blended into the feed. The way in whichsuch feed premixes and complete rations can be prepared and administeredare described in reference books (such as “Applied Animal Nutrition”,W.H. Freedman and CO., San Francisco, U.S.A., 1969 or “Livestock Feedsand Feeding” O and B books, Corvallis, Oreg., U.S.A., 1977).

The compounds covered in this invention may be administered alone or incombination with other antibacterial agents or in combination with apharmaceutically acceptable carrier of dilutent. The compounds of theinvention may be administered intravenously, intramuscularly,intraperitoneally, subcutaneously, topically, orally, or by otheracceptable means. The compounds may be used to treat bacterialinfections in mammals (i.e., humans, livestock, and domestic animals),birds, lizards, and any other organism which can tolerate the compounds,and also to inhibit bacterial growth in cell culture. The compounds canalso be used for effects related to their antibacterial activity such asfor increasing the weight gain of livestock.

IV Synthetic Schemes

The subject quinoline-indoles, and congeners thereof, can be preparedreadily from individual heterocyclic components by employing thecross-coupling technologies of Suzuki, Stille, and the like. Thesecoupling reactions are carried out under relatively mild conditions andtolerate a wide range of “spectator” functionality. A number ofillustrative examples are shown below.

a. Illustrative Suzuki Coupling #1

b. Illustrative Suzuki Coupling #2

c. Illustrative Stille Coupling #1

d. Illustrative Stille Coupling #2

e. Illustrative Stille Coupling #3

Members of the general classes of coupling substrates outlinedabove—arylstannanes, arylboronic acids, aryl triflates and arylhalides—are available from the parent heterocycles. In general, thetransformations required to prepare a coupling substrate are reliableand amenable to scale-up. Illustrative examples are shown below.

f. Illustrative Preparation of a 3-Iodoindole

g. Illustrative Preparation of a 2-(Tributylstannyl)quinoline

h. Illustrative Preparation of a 2-(Trifluoromethanesulfonyloxy)pyridine

i. Illustrative Preparation of a 3-Indolylboronic Acid

Quinoline, and congeneric, substrates that will ultimately beincorporated into subject antibacterials can be purchased or preparedfrom readily available starting materials utilizing well-known chemicaltransformations. The following schemes are illustrative of this fact.

j. Illustrative Quinoline Synthesis #1

k. Illustrative Quinoline Synthesis #2

l. Illustrative Quinoline Synthesis #3

m. Illustrative Indole Synthesis

n. Combinatorial Libraries

The compounds of the present invention, particularly libraries ofvariants having various representative classes of substituents, areamenable to combinatorial chemistry and other parallel synthesis schemes(see, for example, PCT WO 94/08051). The result is that large librariesof related compounds, e.g. a variegated library of compounds representedby formula 1 above, can be screened rapidly in high throughput assays inorder to identify potential antibacterial lead compounds, as well as torefine the specificity, toxicity, and/or cytotoxic-kinetic profile of alead compound. For instance, simple turbidimetric assays (e.g. measuringthe A₆₀₀ of a culture), or spotting compounds on bacterial lawns, can beused to screen a library of the subject compounds for those havinginhibitory activity toward a particular bacterial strain.

Simply for illustration, a combinatorial library for the purposes of thepresent invention is a mixture of chemically related compounds which maybe screened together for a desired property. The preparation of manyrelated compounds in a single reaction greatly reduces and simplifiesthe number of screening processes which need to be carried out.Screening for the appropriate physical properties can be done byconventional methods.

Diversity in the library can be created at a variety of differentlevels. For instance, the substrate aryl groups used in thecombinatorial reactions can be diverse in terms of the core aryl moiety,e.g., a variegation in terms of the ring structure, and/or can be variedwith respect to the other substituents.

A variety of techniques are available in the art for generatingcombinatorial libraries of small organic molecules such as the subjectantibacterials. See, for example, Blondelle et al. (1995) Trends Anal.Chem. 14:83; the Affymax U.S. Pat. Nos. 5,359,115 and 5,362,899: theEllman U.S. Pat. No. 5,288,514: the Still et al. PCT publication WO94/08051; Chen et al. (1994) JACS 116:2661: Kerr et al. (1993) JACS115:252; PCT publications WO92/10092, WO93/09668 and WO91/07087; and theLemer et al. PCT publication WO93/20242). Accordingly, a variety oflibraries on the order of about 100 to 1,000,000 or more diversomers ofthe subject antibacterials can be synthesized and screened forparticular activity or property.

In an exemplary embodiment, a library of candidate antibacterialdiversomers can be synthesized utilizing a scheme adapted to thetechniques described in the Still et al. PCT publication WO 94/08051,e.g., being linked to a polymer bead by a hydrolyzable or photolyzablegroup e.g., located at one of the positions of the candidateantibacterials or a substituent of a synthetic intermediate. Accordingto the Still et al. technique, the library is synthesized on a set ofbeads, each bead including a set of tags identifying the particulardiversomer on that bead. The bead library can then be “plated” on a lawnof bacteria for which an inhibitor is sought. The diversomers can bereleased from the bead, e.g. by hydrolysis. Beads surrounded by areas ofno, or diminished, bacterial growth, e.g. a “halo”, can be selected, andtheir tags can be “read” to establish the identity of the particulardiversomer.

EXEMPLIFICATION

The invention now being generally described, it will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

EXAMPLE 1

Indole-3-carboxaldehyde

To a 500 mL round bottom flask containing 250 mL of DMF at 0° C. wasadded 105 mL (1.12 mol) of phosphorous oxychloride dropwise via anaddition funnel. The reaction mixture was stirred for 30 min at 0° C.and then indole (0.51 mol) was added as a solid. The reaction mixturewas heated to 80° C. for 6 h and then cooled in an ice bath. The coldsolidified reaction was quenched with water (˜2 L) until all the solidhad dissolved. The solution was kept cool and the pH was adjusted to ˜11by the addition of 50% NaOH. The precipitate was filtered and washedwith water. The filter cake was dried in vacuo in the presence of P₂O₅to yield crude indole-3-carboxaldehyde (90-95% yield).

EXAMPLE 2

N-Boc-Indole-3-carboxaldehyde

To a 500 mL round bottom flask containing a solution of crudeindole-3-carboxaldehyde (0.5 mol) in 300 mL of DCM was added 6.1 g (0.05mol) of 4-dimethylaminopyridine. The reaction mixture was cooled to 0°C. and 600 mL of a solution of di-tert-butyldicarbonate (1.0 M in THF)was added slowly dropwise via an addition funnel. The reaction mixturewas allowed to warm to room temperature for 6 h. The reaction mixturewas quenched with 1.0 L of water and the organic layer separated. Theorganic layer was washed with 5% HCl (2×1.0 L) and sat. NaCl (1.0 L),dried (MgSO₄), filtered, and concentrated in vacuo. The crude solid waspurified by dissolving it in DCM (Q_(1.0) L) and precipitating it by theaddition of hexanes (−1.0 L) and filtering with a fritted funnel. Thefilter cake was washed with hexanes and dried in vacuo to giveN-Boc-indole-3-carboxaldehyde (80-85% yield).

EXAMPLE 3

N-Tosyl-Indole-3-carboxaldehyde

To a 25 mL round bottom flask containing a solution of crudeindole-3-carboxaldehyde (4.5 mmol) in 10 mL of triethylamine was added1.3 g (6.7 mmol) of tosyl chloride. The reaction mixture was heated to95° C. for 4 h. The reaction mixture was quenched by pouring into 10 mLof ice water and filtered. The solid was washed with water (3×10 mL),triterated with ether (25 mL), and dried in vacuo to giveN-tosyl-indole-3-carboxaldehyde (85-90% yield).

EXAMPLE 4

2-Boc-3-Indolyl)-4-quinolinecarboxylic Acid

To a 500 mL round bottom flask was added 27.2 g (0.31 mol) of pyruvicacid (Lancaster), N-Boc-indole-3-carboxaldehyde (0.16 mol) and 200 mL ofacetic acid. The reaction mixture was heated at 85° C. until all thesolid material had dissolved (−30 min). Then aniline (0.31 mol) wasadded and the reaction mixture was stirred for 90 minutes at 85° C. Theprecipitate was filtered hot in a fritted funnel and washed with aceticacid (2×50 mL) and then with ether (2×50 mL). The solid filter cake wasdried in vacuo to yield 2-(N-Boc-3-indolyl)-4-quinolinecarboxylic Acid(3-50% yield) of pure (>95%) material.

EXAMPLE 5

2-(3-Indolyl)-4-quinolinecarboxylic Acid or Ester

To a 10 mL pear-shaped flask was added2-(N-Boc-3-indolyl)-4-quinolinecarboxylic acid or ester (1 mmol) and 3mL of a 50% mixture of TFA and DCM. The reaction mixture was stirred for30 min at 20° C. The solvent was removed under reduced pressure and theresidual solid lyophilized to give 2-(3-indolyl)-4-quinolinecarboxylicacid or ester (95-100% yield).

EXAMPLE 6

Resin-Bound Diamine

To a 200 mL glass frit flask was added 10 g (8.0 mmol) of Wang resin,13.0 g (80 mmol) of CDI, and 100 mL of THF. The reaction mixture wasagitated on an orbital shaker for 24 h. The reaction mixture wasfiltered and the resin washed with THF (3×100 mL). To the glass fritflask containing the activated resin was added diamine (80 mmol)dissolved in 100 mL of THF. The reaction mixture was agitated on anorbital shaker for 24 h. The reaction mixture was filtered and the resinwashed with THF (3×100 mL), DMF (3×100 mL), MeOH (3×100 mL), and DCM(3×100 mL) and dried under vacuum to give 11.3 g (0.70 mmol/g) of resin.

EXAMPLE 7

Resin-Bound 2-(3-Indolyl)quinoline-4-carboxylate or -carboxamide

To a 10 mL pear-shaped flask was added2-(3-indolyl)-4-quinolinecarboxylic acid (0.2 mmol), 104 mg of PyBOP®(0.2 mmol), 1 mL of DMF and 44 μL of N-methylmorpholine (0.4 mmol). Thereaction mixture was stirred for 10 min and then added to a 3 mL plastictube fitted with a frit containing 100 mg of Wang or Rink resin (0.08mmol) and ˜1 mg of DMAP (0.001 mmol). The reaction mixture was agitatedovernight on an orbital shaker at ambient temperature. The solvent wasremoved by filtration and the resin washed successively with DMF (3×3mL), MeOH (3×3 mL), and DCM (3×3 mL) and dried under vacuum to giveresin-bound 2-(3-indolyl)quinoline-4-carboxylate or -carboxamide.

EXAMPLE 8

Resin-Bound 2-(3-Indolyl)quinoline-4-aminoalkylcarboxamide

To a 10 mL pear-shaped flask was added of2-(3-indolyl)-4-quinolinecarboxylic acid (0.088 mmol), 46 mg of PyBOP®(0.088 mmol), 1 mL of DMF and 19 μL of N- methylmorpholine (0.176 mmol).The reaction mixture was stirred for 10 min and then added to a 3 mLplastic tube fitted with a frit containing 50 mg of diamine-capped resin(0.035 mmol) and ˜1 mg of DMAP (0.001 mmol). The reaction mixture wasagitated overnight on an orbital shaker at ambient temperature. Thesolvent was removed by filtration and the resin washed successively withDMF (3×3 mL), MeOH (3×3 mL), and DCM (3×3 mL) and dried under vacuum togive resin-bound 2-(3-indolyl)quinoline-4-aminoalkylcarboxamide.

EXAMPLE 9

2-Indolyl)quinoline-4-aminoalkylcarboxamide

To a 3 mL plastic tube fitted with a frit containing 50 mg ofresin-bound 2-(3-indolyl)quinoline-4-carboxamide (0.035 mmol) was added1 mL of a 50% mixture of TFA and DCM. The reaction mixture was agitatedon an orbital shaker for 30 min. The mixture was filtered and the resinwashed with DCM (3×3 mL). The organic solutions were combined andevaporated by a stream of N₂. The residual solid was lyophilized to give2-(3-indolyl)quinoline-4-aminoalkylcarboxamide (80-100% yield).

EXAMPLE 10

2-3-Indolyl)quinoline-4-carboxylic Acid or Amide

To a 3 mL plastic tube fitted with a frit containing 50 mg ofresin-bound 2-(3-indolyl)quinoline-4-carboxylate (0.035 mmol) was added1 mL of a 50% mixture of TFA and DCM. The reaction mixture was agitatedon an orbital shaker for 30 min. The mixture was filtered and the resinwashed with DCM (3×3 mL). The organic solutions were combined andevaporated by a stream of nitrogen. The residual solid was lyophilizedto give 2-(3-indolyl)quinoline-4-carboxylic acid or amide (80-100%yield).

EXAMPLE 11

Resin-Bound Propargylaminoalkynyl-Substituted2-(3-Indolyl)quinoline-4-aminoalkylcarboxamide

To a 3 mL plastic tube fitted with a frit containing 50 mg (0.035 mmol)of resin-bound 2-(3-indolyl)-(5,6,7, or8)-iodoquinoline-4-aminoalkylcarboxamide was added 6.5 mg ofpalladium(II) acetate (0.028 mmol), 0.3 mg of copper(I) iodide (1.8umol), 11 mg of triphenylphosphine (0.042 mmol), 1 mL of THF, 25 μL ofpropargyl bromide (0.28 mmol) and amine (0.7 mmol). The reaction mixturewas agitated on an orbital shaker for 12 h. The reaction mixture wasfiltered and the resin washed with THF (3×3 mL), DMF (3×3 mL), MeOH (3×3mL), DCM (3×3 mL), and dried under vacuum to give resin-boundpropargylaminoalkynyl-substituted2-(3-indolyl)quinoline-4-aminoalkylcarboxamide.

EXAMPLE 12

Resin-Bound Aryl-Substituted2-(3-Indolyl)quinoline-4-aminoalkylcarboxamide

To a 3 mL plastic tube fitted with a frit containing 50 mg (0.035 mmol)of resin-bound 2-(3-indolyl)-(5,6,7, or8)-bromoquinoline-4-aminoalkylcarboxamide was added arylboronic acid(0.35 mmol), 4.3 mg of palladium tetrakistriphenylphosphine (3.5 umol) 1mL of DMF, and 104 μL of triethylamine (0.75 mmol). The reaction mixturewas agitated on an orbital shaker for 12 h in a Fischer heating block at60° C. The reaction mixture was filtered and the resin washed with DMF(3×3 mL), MeOH (3×3 mL), DCM (3×3 mL), and dried under vacuum to giveresin-bound aryl-substituted2-(3-indolyl)quinoline-4-aminoalkylcarboxamide.

EXAMPLE 13

Resin-Bound 2-(3-N-Methylindolyl)quinoline-4-carboxylate

To a 3 mL plastic tube fitted with a frit containing 500 mg (0.35 mmol)of resin-bound 2-(3-indolyl)quinoline-4-carboxylate was added 342 mg ofcesium carbonate (1.1 mmol), 3 mL of DMF, and 440 μL (7.0 mmol) ofmethyl iodide. The reaction mixture was agitated on an orbital shakerfor 4 h. The resin was filtered and washed with DMF (3×3 mL), H₂0 (3×3mL), MeOH (3×3 mL), and DCM (3×3 mL) and dried under vacuum. Thisprocess was repeated once to give resin-bound2-(3-N-methylindolyl)quinoline-4-carboxylate.

EXAMPLE 14

Quinoline-N-oxide

To a 100 mL round bottom flask containing a solution of quinoline (12.2mmol) in 50 mL of DCM was added 5.3 g of m-CPBA (30.6 mmol). Thereaction mixture was stirred for 24 h. The reaction mixture was thendiluted DCM (100 mL), washed with 5% NaOH (2×100 mL), dried (MgSO₄),filtered, and concentrated in vacuo to give solid quinoline-N-oxide(90-95% yield).

EXAMPLE 15

2-(3-Indolyl)quinoline

To a solution of quinoline-N-oxide (0.5 mmol) in 2 mL DCM at 0° C. in a3 mL plastic tube fitted with a frit was added 58 uL of benzoyl chloride(0.5 mmol). The reaction mixture was stirred for 15 min at 0° C. andthen indole (0.5 mmol) was added. The reaction was warmed to 20 ° C. andstirred for 4 h. The solid precipitate was filtered and washed with DCM(3×2 mL) to give solid 2-(3-indolyl)quinoline (6-100% yield).

EXAMPLE 16

2-(3-N-Methylindolyl)quinoline

To a 10×130 mm test tube containing 2-(3-indolyl)quinoline (0.1 mmol) in1 mL of DMF was added 130 mg of cesium carbonate (0.4 mmol and 12 μL(0.2 mmol) of methyl iodide. The reaction mixture was agitated on anorbital shaker in a Fischer heating block at 40° C. for 12 h. Thereaction mixture was filtered and the organic layer diluted with DCM (4mL) and washed with water (1×5 mL). The organic solvent was evaporatedunder a stream of nitrogen and the residual solid lyophilized to givesolid 2-(3-N-methylindolyl)quinoline (95-100% yield).

EXAMPLE 17

N-Acyl-Substituted 2-(3-Indolyl)quinoline-4-aminoalkylcarboxamide

To a 9 mL test tube containing2-(3-indolyl)quinoline-4-aminoalkylcarboxamide (0.1 mmol) in 2 mL ofEtOAc and 2 mL of sat. NaHCO₃ was added 300 μL of a solution of acidchloride or chloroformate (0.3 mmoL) in 0.3 mL of DCM. The reactionmixture was agitated for 4 h on an orbital shaker. The layers wereallowed to separate and the top organic layer was pipeted off and thesolvent removed under reduced pressure to give N-acyl-substituted2-(3-indolyl)quinoline-4-aminoalkylcarboxamide (60-80% yield).

EXAMPLE 18

N-Alkylsulfonyl-Substituted2-(3-Indolyl)quinoline-4-aminoalkylcarboxamide

To a 9 mL test tube containing2-(3-indolyl)quinoline-4-aminoalkylcarboxamide (0.1 mmol) in 2 mL ofEtOAc and 2 mL of sat. NaHCO₃ was added 300 μL of a solution of analkylsulfonyl chloride (0.3 mmoL) in 0.3 mL of DCM. The reaction mixturewas agitated for 4 h on an orbital shaker. The layers were allowed toseparate and the top organic layer was pipeted off. To the organicsolution was added −50 mg of aminomethyl resin and the mixture agitatedon an orbital shaker for 1 h. The mixture was filtered and the solventremoved under reduced pressure to give N-alkylsulfonyl-substituted2-(3-indolyl)quinoline-4-aminoalkylcarboxamide (60-80% yield).

EXAMPLE 19

N-Alkylurea-Substituted 2-(3-Indolyl)quinoline-4-aminoalkylcarboxamide

To a 9 mL test tube containing2-(3-indolyl)quinoline-4-aminoalkylcarboxamide (0.1 mmol) in 2 mL of THFwas added 300 μL of a solution of alkylisocyanate (0.3 mmoL) in 0.3 mLof THF. The reaction mixture was agitated for 4 h on an orbital shaker.To the reaction mixture was added ˜50 mg of aminomethyl resin and themixture agitated on an orbital shaker for 1 h. The mixture was filteredand the solvent removed under reduced pressure to giveN-alkylurea-substituted 2-(3-indolyl)quinoline-4-aminoalkylcarboxamide(60-80% yield).

EXAMPLE 20

N-Terminal Resin-Bound Amino Acid

To a 10 mL pear-shaped flask was added Fmoc protected amino acid (0.4mmol), 250 mg of PyBOP (0.4 mmol), 2 mL of DMF and 81 uL ofN-methylmorpholine (0.8 mmol). The reaction mixture was stirred for 10min and then added to a 3 mL plastic tube fitted with a frit containing50 mg of Rink or Wang resin (0.08 mmol) and 1 mg of DMAP (0.001 mmol).The reaction mixture was agitated overnight on an orbital shaker atambient temperature. The solvent was removed by filtration and the resinwashed successively with DMF (3×3 mL), MeOH (3×3 mL), and DCM (3×3 mL)and dried under vacuum to give resin-bound Fmoc protected amino acid.The resin was then suspended in 2 mL of a 30% solution of piperidine inDCM. The resin was then filtered and washed with DCM (3×3 mL) to giveN-terminal resin bound amino acid.

EXAMPLE 21

Resin-Bound 2-(3-Indolyl)quinoline-4-amino Acid

To a 10 mL pear-shaped flask was added of2-(3-indolyl)-4-quinolinecarboxylic acid (0.088 mmol), 46 mg of PyBOP(0.088 mmol), 1 mL of DMF and 19 uL of N-methylmorpholine (0.176 mmol).The reaction mixture was stirred for 10 min and then added to a 3 mLplastic tube fitted with a frit containing 50 mg of N-terminalresin-bound amino acid (0.035 mmol) and ˜1 mg of DMAP (0.001 mmol). Thereaction mixture was agitated overnight on an orbital shaker at ambienttemperature. The solvent was removed by filtration and the resin washedsuccessively with DMF (3×3 mL), MeOH (3×3 mL), and DCM (3×3 mL) anddried under vacuum to give resin-bound 2-(3-indolyl)quinoline-4-aminoacid.

EXAMPLE 22

2-(3-Indolyl)quinoline-4-amino acid

To a 3 mL plastic tube fitted with a frit containing 50 mg ofresin-bound 2-(3-indolyl)quinoline-4-amino acid (0.035 mmol) was added 1mL of a 50% mixture of TFA and DCM. The reaction mixture was agitated onan orbital shaker for 30 min. The mixture was filtered and the resinwashed with DCM (3×3 mL). The organic solutions were combined andevaporated by a stream of N₂. The residual solid was lyophilized to give2-(3-indolyl)quinoline-4-amino acid (80-100% yield).

EXAMPLE 23

Methyl 2-(3-indolyl)-4-quinolinecarboxylate

To a 10 mL pear-shaped flask was added2-(3-indolyl)-4-quinolinecarboxylic acid (1 mmol) and 2 mL ofacetonitrile followed by a solution of diazomethane (5 mmol) in 2 mL ofether. The reaction mixture was stirred for 1 h and the solvent removedin vacuo to give methyl-2-(3-indolyl)-4-quinolinecarboxylate (95-100%yield).

EXAMPLE 24

Resin-Bound 4-(Aminoalkyl)-2-(3-indolyl)quinoline

To a 3 mL plastic tube fitted with a frit containing 50 mg of N-terminalresin-bound 4-aminoalkylcarboxamide (0.035 mmol) was added 1.0 mL a 1.0M solution of borane in THF (1.0 mmol). The reaction mixture wasagitated for 1 h at 50° C. on an orbital shaker. The reaction mixturewas cooled and then quenched by slow addition of methanol. The mixturewas filtered and the resin washed with MeOH (3×3 mL) and DCM (3×3 mL).To the resin was added 2 mL of a 0.6 M solution of DBU in a 9:1 mixtureof DMF and MeOH. The reaction mixture was agitated for 2 h at 20° C. onan orbital shaker. The mixture was filtered and the resin washed withDMF, (3×3 mL), MeOH (3×3 mL), and DCM (3×3 mL) and dried under vacuum togive resin-bound 4-(aminoalkyl)-2-(3-indolyl)quinoline.

EXAMPLE 25

Synthesis of Compound 154

2: A solution of 4-(aminomethyl)benzoic acid (1 g, 6.6 mmol) in methanol(20 mL) saturated with HCl was heated at reflux overnight. The solutionwas concentrated, diluted with 15 ml of saturated aqueous sodiumbicarbonate, and subsequently extracted with dichloromethane (3×50 mL).The combined organic layers were dried over magnesium sulfate, filtered,and concentrated under vacuum to give 622 mg of a yellow oil. This oilwas dissolved in dichloromethane (10 mL); triethylamine (532.6 mg) anddi-t-butyl dicarbonate (4.88 ml, 1M solution in THF) were added to thissolution. The reaction mixture was stirred under N₂ for 1 h. Saturatedsodium bicarbonate (10 mL) was added to the mixture, and it wasextracted with dichloromethane (3×50 mL). The combined organic layerswere dried over magnesium sulfate, filtered and concentrated undervacuum to give 1 g of a white powder. The white powder (750 mg, 4.54mmol) was dissolved in THF (20 mL) and the solution cooled to 0° C.under N₂. Lithium aluminum hydride (258 mg) was added and, after 2 h,saturated aqueous sodium bicarbonate (15 mL) was added, followed by 1 Nsodium hydroxide (2 mL). The mixture was extracted with ethyl acetate(3×15 mL), and the combined organic layers were dried over magnesiumsulfate, filtered and concentrated under vacuum to yield 600 mg whitesolid. The alcohol (400 mg, 1.64 mmol) was dissolved in THF (20 mL), andthe solution was cooled to 0° C. under N₂. Triphenylphosphine (856 mg,2.26 mmol) was added slowly, followed by imidazole(220 mg, 2.26 mmol)and iodine (827.4 mg, 2.26 mmol); the resulting mixture was stirred for1 h. The reaction mixture was filtered, and the filtrate wasconcentrated. The residue was purified via silica gel flashchromatography (EtOAc-hexane, 1:4) to afford a white solid (300 mg).

4: Carboxylic acid 3 (400 mg, 0.749 mmol) was dissolved in THF (10 mL)and lithiumaluminum hydride(85.27 mg, 2.247 mmol) was added. Theresulting suspension was heated at reflux overnight under nitrogen.Saturated aqueous sodium bicarbonate (20 mL) was added, and theresulting mixture was extracted with dichloromethane (3×50 mL). Thecombined organic layers were dried over magnesium sulfate, filtered, andconcentrated under vacuum. The crude residue (240 mg, 0.57 mmol) wasdissolved in dichloromethane (5 mL), and the solution was cooled to 0°C. under N₂. 2,6-Lutidine (183.24 mg, 1.71 mmol) andtert-butyldimethylsilyl trifluoromethanesulfonate(452.02 mg) were added,and the mixture was stirred for 2 h. Saturated aqueous sodiumbicarbonate (20 mL) was added, and the mixture was stirred for 30minutes at room temperature. The reaction mixture was extracted withdichloromethane (3×50 mL), and the combined organic layers were driedover magnesium sulfate, filtered and concentrated under vacuum. Thecrude material was dissolved in dichloromethane (3 mL), and cooled to 0°C. under N₂. DMAP (7 mg, 0.057 mmol) and di-tert-butyl dicarbonate (0.74ml, 0.741 mmol, 1 M in THF) were added to the solution. After beingstirred for 30 minutes, saturated aqueous sodium bicarbonate (10 mL) wasadded, and the resulting mixture was extracted with dichloromethane(3×30 mL). The combined the organic layers were dried over magnesiumsulfate, filtered and concentrated under vacuum. The crude material wasdissolved in THF (5 mL), and tetrabutylammonium fluoride (0.684 mL, 1 Min tetrahydrofuran) was added. After 1 h at room temperature, thereaction mixture was concentrated under vacuum. Saturated aqueous sodiumbicarbonate (10 mL) was added, and the mixture was extracted withdichloromethane (3×30 mL). The combined organic layers were dried overmagnesium sulfate, filtered, and concentrated in vacuo. The crudematerial was purified via silica gel flash chromatography (EtOAc-MeOH,19:1) to give the desired compound (130 mg).

Y: 44%.

MS: 520.90, 420.90, 404.

5: Compound 4 (120 mg, 0.23 mmol) was dissolved in anhydrousdimethylformamide (1 mL), and sodium hydride (12 mg, 0.299 mmol, 60%dispersion) was added. The reaction mixture was heated at 80° C. for 1h. Saturated aqueous sodium bicarbonate (10 mL) was added, and themixture was extracted with dichloromethane (3×30 mL). The combinedorganic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo to give 5 (140 mg).

Y: 82%

MS: 741.74

6: Compound 5 (140 mg, 0.19 mmol) was dissolved in dichloromethane (5mL) and 30% trifluoroacetic acid was added; the resulting solution wasstirred at room temperature for 45 minutes. The reaction mixture wasconcentrated in vacuo, and the residue was combined with saturatedaqueous sodium bicarbonate (5 mL), and this mixture was extracted withdichloromethane (3×30 mL). The combined organic layers were dried overmagnesium sulfate, filtered, and concentrated in vacuo to give 6 (80mg).

Y: 78%

MS: 541.83

Example 26

Synthesis of Compound 48

The carboxylic acid (500 mg, 1.366 mmol) was dissolved indimethylformamide (3 mL), and Py-Bop (852 mg, 1.63 mmol), and N-methylmorpholine (164 mg, 1.63 mmol) were added, followed by stirring for 30minutes. p-Anisidine (200 mg, 1.63 mmol) was added, and the mixture wasstirred overnight. Water (30 mL) was added dropwise to the reactionmixture and a precipitate formed. The reaction mixture was filtered andthe collected solid was dried in vacuo to give 48 (350 mg).

Y: 54%

MS: 470

EXAMPLE 27

Synthesis of Compound 87

Resin-bound 2-hydroxyquinoline-4-carboxylic acid (5 mmol) was suspendedin dichloromethane (150 mL), pyridine (8.4 g, 1100 mmol) was added, andthe solution was cooled to 0° C. Trifluoromethanesulfonic anhydride(14.1 g, 50 mmol) was added dropwise and the suspension was shaken for 1h. The mixture was filtered, and the resin was washed withdichloromethane, THF and methanol. The resin (0.059 mmol) was suspendedin THF (10 mL), and 2-naphtaleneboronic acid (3 0.44 mg, 0. 177 mmol), 2M aqueous sodium carbonate (18.76 μL, 0.177 mmol), andtetrakis(triphenylphosphine)palladium(0) (10 mg, 0.008 minol) were addedin series; the mixture was shaken overnight at 60° C. The suspension wasfiltered, washed with THF, dichloromethane, and methanol. The resin wassuspended in dichioromethane (5 mL), 30% TFA was added, and thesuspension was shaken for 30 minutes. The suspension was filtered, theresin was rinsed with dichloromethane and the combined organics wereconcentrated in vacuo to give an orange solid (20 mg).

Y: 83%

MS: 418.3

EXAMPLE 28

Synthesis of Compound 92

The amine (25 mg, 0.058 mmol) was dissolved in chloroform (5 mL),followed by addition of 37% formaldehyde (18.46 μL, 0.24 mmol) andformic acid (8.44 μL, 0.24 mmol). The mixture was heated at reflux for 6h, and allowed to cool to rom temperature. Saturated aqueous sodiumbicarbonate (5 mL) was added, and the mixture was extracted withdichloromethane (3×15 mL). The combined organic layers were dried overmagnesium sulfate, filtered and concentrated in vacuo. Methanol (4 mL)was added to the residue to give a beige powder (15 mg).

Y: 50%

MS: 514

EXAMPLE 29

Synthesis of Compound 91

The amine (30 mg, 0.06 mmol) was suspended in methanol (5 mL), and 1drop of concentrated HCl (1 drop) was added to give a soluble ammoniumion. Adam's catalyst (5 mg, PtO₂) was added, and the mixture was shakenovernight under an atmosphere of hydrogen (30 psi). The reaction mixturewas filtered, and the filtrate was concentrated in vacuo to give the2-(5-bromo-3-indolyl)tetrahydroquinoline (20 mg).

Y: 81%

MS: 411.17

EXAMPLE 30

Synthesis of Compound 267

A mixture of 6-chloro-2-[6-fluoro-3-indolyl]quinoline (29.6 mg),prepared utilizing a procedure previous described, and sodium hydride (4mg) in dimethylacetamide (2 mL) was heated at 60° C. under an inert (Ar)atmosphere for 30 min. Next, N-(4-bromobutyl)phthalimide (29.6 mg) wasadded and heating at 60° C. was continued for 24 h. The reaction mixturewas allowed to cool to room temperature before being quenched withwater. The mixture was extracted several times with dichloromethane. Theorganic extracted were combined, washed with brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated to give a yellow oil. Theoil was purified by spin plate chromatography on silica gel eluting withhexane/ethyl acetate (70:30) to give 10 mg of 267 as a tan solid. ¹H NMR(300 MHz, CDCl₃): δ 1.75-1.81 (m, 2H), 1.90-1.98 (m, 2H); 3.74 (t, 2H,J=6.6 Hz); 4.21 (t, 2H, J=6.6 Hz); 7.06 (d, 2H, J=9.3 Hz); 7.61 (dd, 1H,J=8.9 Hz, J₂=2.7 Hz); 7.69-8.06 (m, 9H); 8.73 (dd, 1H, J₁=8.7 Hz, J₂=5.7Hz).

EXAMPLE 31

Determination of MIC Values

Stock solutions of compounds are prepared with a concentration of 10mg/mL. These solutions are then diluted 1:4 to give a concentration of2.5 mg/mL. The compounds are then serially diluted 1:2 for 6 iterations.The concentrations made for each compound are 2.5, 1.25, 0.625, 0.3125,0.156, 0.078, and 0.039 mg/mL. A control sample (no compound) is runalong with each compound tested. All dilutions are made in DMSO.

All wells of a 96 well microtiter plate are filled with 100 PL of BHI(Brain-Heart Infusion) broth. Columns on the plate are labeled 1-12, androws are labeled A-H. Each column of wells is used to test one series ofdiluted compounds. Into each well of 100 μL of BHI broth, 1 μL ofdiluted compound is placed for a 1:100 dilution. This makes the finalconcentration of each drug series 25, 12.5, 6.25, 3.125, 1.56, 0.78,0.39, and 0 Hg/mL.

Test Organism: A sterile 15 mL screw cap tube is filled wth 3 mL of BHIbroth. Next, 2-3 colonies of test organism are inoculated into the tube.The tube is then incubated at 37° C. in a CO₂ (approx. 7%) atmospherejar. The organisms are allowed to grow to the density of a 0.5 McFarlandstandard (10⁸ cells/mL). The organism is then inoculated into each wellof the microtiter plate containing the diluted compounds to be testedfor MIC. The inoculum is 1 μL in volume and represents 10⁵ to 10⁶cells/mL.

After inoculation the plates are covered and incubated at 37° C. andapprox. 7-10% CO₂ atmosphere overnight (about 16 hours). The plates arethen observed for growth, the well with the lowest concentration of drugand no observable growth represents the well determining the MIC.

EXAMPLE 32

Table of MIC Values (μg/mL) for Subject Compounds

Cmpd. S. # STRUCTURE MRSA VREF pneu 1

> 25 > 25 2

< 25 < 25 3

< 25 < 25 4

< 25 <  7 5

<  7 <  7 6

> 25 > 25 7

> 25 > 25 8

> 25 > 25 9

<  7 <  7 <  7 10

< 25 < 25 11

< 25 < 25 12

> 25 > 25 13

< 7 < 25 14

< 25 < 25 15

< 25 > 25 16

<  7 < 25 17

< 25 > 25 18

> 25 > 25 19

< 25 < 25 20

< 25 < 25 21

> 25 > 25 22

> 25 > 25 23

> 25 > 25 24

> 25 > 25 25

> 25 > 25 26

< 25 < 25 27

> 25 > 25 28

< 25 < 25 29

< 25 < 25 30

< 25 > 25 31

< 25 < 25 32

< 25 < 25 33

<  7 <  7 34

< 25 < 25 35

< 25 > 25 36

< 25 < 25 37

<  7 > 25 38

<  7 > 25 39

<  7 <  7 40

> 25 > 25 41

< 25 < 25 42

> 25 < 25 43

< 25 < 25 44

< 25 < 25 45

> 25 > 25 46

< 25 < 25 47

< 25 < 25 48

<  7 > 25 <  7 49

<  7 <  7 50

<  7 < 25 51

<  7 <  7 52

< 25 < 25 53

<  7 <  7 <  7 54

<  7 <  7 55

<  7 <  7 56

< 25 < 25 57

< 25 < 25 58

< 25 < 25 59

<  7 <  7 60

< 25 < 25 61

<  7 <  7 <  7 62

> 25 > 25 63

> 25 > 25 64

> 25 > 25 65

< 25 <  7 66

> 25 > 25 67

<  7 <  7 68

<  7 <  7 69

> 25 > 25 70

<  7 < 25 71

< 25 > 25 72

> 25 > 25 73

< 25 < 25 74

<  7 < 25 75

> 25 > 25 76

> 25 > 25 > 25 77

> 25 > 25 78

> 25 > 25 79

> 25 > 25 80

< 25 < 25 81

> 25 > 25 82

> 25 > 25 83

> 25 > 25 84

<  7 < 25 85

<  7 < 25 86

> 25 > 25 87

< 25 < 25 88

> 25 > 25 89

< 25 > 25 90

< 25 <  7 91

> 25 > 25 92

< 25 < 25 93

> 25 > 25 94

> 25 > 25 95

> 25 > 25 96

<  7 <  7 <  7 97

> 25 > 25 98

< 25 < 25 99

< 25 < 25 100

> 25 > 25 101

<  7 <  7 102

<  7 <  7 <  7 103

<  7 <  7 <  7 104

<  7 <  7 <  7 105

> 25 < 25 106

< 25 < 25 107

<  7 <  7 <  7 108

<  7 <  7 <  7 109

<  7 <  7 <  7 110

<  7 <  7 <  7 111

<  7 <  7 <  7 112

<  7 <  7 <  7 113

<  7 <  7 <  7 114

<  7 <  7 <  7 115

<  7 <  7 <  7 116

<  7 <  7 <  7 117

<  7 <  7 <  7 118

<  7 <  7 <  7 119

<  7 < 25 <  7 120

<  7 <  7 121

<  7 <  7 122

<  7 <  7 <  7 123

<  7 <  7 <  7 124

<  7 <  7 <  7 125

<  7 <  7 126

<  7 <  7 127

<  7 <  7 <  7 128

<  7 <  7 <  7 129

<  7 <  7 130

<  7 <  7 131

<  7 < 25 <  7 132

<  7 <  7 <  7 133

<  7 <  7 <  7 134

<  7 <  7 <  7 135

<  7 <  7 136

<  7 <  7 <  7 137

< 25 < 25 138

<  7 <  7 <  7 139

<  7 <  7 <  7 140

> 25 < 25 141

> 25 > 25 142

<  7 <  7 <  7 143

<  7 <  7 <  7 144

<  7 < 25 < 25 145

<  7 < 25 146

<  7 < 25 147

<  7 <  7 148

<  7 < 25 149

<  7 > 25 150

> 25 > 25 151

> 25 > 25 > 25 152

<  7 < 25 153

>  7 > 25 <  7 154

<  7 <  7 <  7 155

> 25 > 25 156

> 25 > 25 157

> 25 > 25 158

<  7 <  7 <  7 159

<  7 < 25 < 25 160

< 25 < 25 161

<  7 <  7 <  7 162

> 25 > 25 163

< 25 > 25 > 25 164

<  7 < 5 <  7 165

<  7 <  7 <  7 166

> 25 > 25 167

> 25 > 25 168

<  7 > 25 <  7 169

<  7 > 25 <  7 170

<  7 > 25 <  7 171

<  7 <  7 <  7 172

<  7 > 25 <  7 173

<  7 > 25 <  7 174

<  7 > 25 < 25 175

<  7 < 25 <  7 176

> 25 > 25 177

> 25 > 25 178

> 25 > 25 179

> 25 > 25 180

> 25 > 25 181

<  7 < 25 <  7 182

> 25 > 25 183

< 25 > 25 > 25 184

> 25 > 25 <  7 185

< 25 > 25 186

> 25 > 25 187

> 25 > 25 188

> 25 > 25 189

< 25 < 25 190

> 25 > 25 191

<  7 < 25 <  7 192

> 25 > 25 193

<  7 <  7 <  7 194

<  7 > 25 <  7 195

> 25 > 25 > 25 196

<  7 > 25 < 25 197

<  7 > 25 198

> 25 > 25 199

> 25 > 25 > 25 200

<  7 > 25 > 25 201

<  7 < 25 <  7 202

<  7 > 25 <  7 203

> 25 > 25 204

<  7 < 25 <  7 205

< 25 < 25 206

> 25 > 25 207

> 25 < 25 208

<  7 < 25 < 25 209

<  7 <  7 <  7 210

<  7 > 25 211

< 25 > 25 > 25 212

> 25 > 25 213

< 25 < 25 214

< 25 > 25 215

<  7 < 25 216

< 25 > 25 217

< 25 < 25 <  7 218

<  7 > 25 > 25 219

> 25 > 25 < 25 220

< 25 > 25 221

<  7 <  7 <  7 222

> 25 > 25 223

<  7 <  7 <  7 224

<  7 <  7 <  7 225

<  7 <  7 <  7 226

< 25 < 25 <  7 227

<  7 <  7 <  7 228

> 25 > 25 > 25 229

<  7 <  7 <  7 230

<  7 <  7 <  7 231

<  7 <  7 <  7 232

<  7 <  7 <  7 233

> 25 < 25 < 25 234

> 25 > 25 > 25 235

<  7 <  7 < 7 236

<  7 <  7 <  7 237

<  7 <  7 238

<  7 < 25 <  7 239

<  7 <  7 > 25 240

<  7 < 25 > 25 241

<  7 <  7 <  7 242

<  7 < 25 <  7 243

<  7 <  7 <  7 244

<  7 <  7 <  7 245

<  7 <  7 <  7 246

<  7 <  7 <  7 247

<  7 <  7 <  7 248

<  7 <  7 <  7 249

<  7 <  7 <  7 250

<  7 <  7 <  7 251

<  7 <  7 <  7 252

<  7 <  7 <  7 253

<  7 < 25 <  7 254

<  7 <  7 <  7 255

<  7 <  7 256

<  7 <  7 <  7 257

<  7 <  7 <  7 258

<  7 <  7 <  7 259

<  7 <  7 <  7 260

< 25 < 25 < 25 261

< 25 < 25 < 25 262

<  7 <  7 <  7 263

< 25 < 25 <  7 264

<  7 < 25 265

<  7 <  7 266

<  7 > 25 <  7 267

> 25 > 25 268

<  7 <  7 269

<  7 <  7 270

< 25 < 25 > 25 271

<  7 < 25 <  7 272

<  7 <  7 <  7 273

<  7 <  7 <  7 274

< 25 > 25 <  7 275

<  7 <  7 < 25 276

<  7 <  7 > 25 277

<  7 <  7 <  7 278

<  7 <  7 <  7 279

<  7 <  7 <  7 280

<  7 <  7 <  7 281

< 25 > 25 > 25 282

<  7 <  7 <  7 283

<  7 <  7 <  7 284

<  7 [CRSA] <  7 <  7 285

<  7 <  7 <  7 286

< 7 [CRSA] <  7 <  7 287

<  7 > 25 <  7 288

<  7 <  7 <  7 289

<  7 > 25 <  7 290

> 25 > 25 > 25 291

> 25 > 25 > 25 292

> 25 > 25 > 25 293

<  7 <  7 <  7 294

<  7 <  7 <  7 295

<  7 <  7 <  7 296

< 7 [CRSA] <  7 <  7 297

< 25 < 25 < 25 298

<  7 <  7 <  7 299

<  7 <  7 <  7 300

<  7 <  7 < 25 301

<  7 < 25 < 25 302

<  7 <  7 <  7 303

<  7 > 25 <  7 304

<  7 <  7 <  7 305

<  7 <  7 <  7 306

<  7 <  7 <  7 307

<  7 <  7 <  7 308

<  7 <  7 <  7 309

> 25 > 25 > 25 310

< 25 > 25 < 25 311

> 25 > 25 > 25 312

<  7 <  7 <  7 313

<  7 <  7 <  7 314

<  7 <  7 <  7 315

<  7 <  7 <  7 316

<  7 <  7 <  7 317

<  7 <  7 <  7 318

<  7 <  7 <  7 319

<  7 < 25 <  7 320

< 7 [CRSA] <  7 <  7 321

<  7 <  7 <  7 322

<  7 <  7 <  7 323

< 7 [CRSA] < 25 <  7 324

> 25 [CRSA] > 25 > 25 325

<  7 <  7 <  7 326

<  7 <  7 <  7 327

< 25 > 25 <  7 328

> 25 > 25 <  7 329

< 7 [CRSA] <  7 <  7 330

<  7 <  7 <  7 331

<  7 <  7 <  7 332

<  7 <  7 <  7 333

<  7 <  7 <  7 334

<  7 <  7 <  7 335

<  7 <  7 <  7 336

<  7 <  7 <  7 337

> 25 > 25 > 25 338

< 25 > 25 <  7 339

<  7 <  7 <  7 340

<  7 <  7 <  7 341

<  7 <  7 <  7 342

<  7 > 25 <  7 343

<  7 > 25 <  7 344

<  7 > 25 <  7 345

<  7 > 25 <  7 346

< 25 > 25 < 25 347

< 25 > 25 < 25 348

<  7 > 25 <  7 349

> 25 > 25 > 25 350

> 25 > 25 > 25 351

<  7 > 25 <  7 352

<  7 > 25 <  7 353

> 25 > 25 > 25 354

> 25 > 25 > 25 355

> 25 > 25 > 25 356

<  7 <  7 <  7 357

<  7 <  7 <  7 358

<  7 <  7 <  7 359

<  7 <  7 <  7 360

<  7 <  7 <  7 361

> 25 > 25 > 25 362

> 25 > 25 > 25 363

<  7 <  7 <  7 364

<  7 < 25 <  7 365

<  7 <  7 <  7 366

> 25 > 25 > 25 367

> 25 > 25 > 25 368

<  7 <  7 <  7 369

<  7 <  7 <  7 370

<  7 <  7 <  7 371

<  7 <  7 <  7 372

<  7 < 25 <  7 373

<  7 <  7 <  7 374

<  7 <  7 <  7 375

> 25 > 25 > 25 376

< 25 < 25 <  7 377

<  7 <  7 <  7 378

<  7 <  7 <  7 379

<  7 <  7 <  7 380

<  7 <  7 <  7 381

> 25 > 25 > 25 382

> 25 > 25 > 25 383

> 25 > 25 > 25 384

<  7 > 25 <  7 385

> 25 > 25 > 25 386

> 25 > 25 > 25 387

> 25 > 25 > 25 388

> 25 > 25 > 25 389

<  7 <  7 < 25 390

< 25 <  7 <  7 391

<  7 <  7 <  7 392

<  7 <  7 <  7 393

<  7 < 25 < 25 394

> 25 > 25 > 25 395

<  7 < 25 < 25 396

> 25 > 25 > 25 397

<  7 <  7 <  7 398

<  7 <  7 <  7 399

<  7 <  7 <  7 400

<  7 <  7 <  7 401

<  7 <  7 <  7 402

<  7 <  7 <  7 403

<  7 <  7 <  7 404

<  7 <  7 <  7 405

< 25 < 25 < 25 406

<  7 <  7 <  7 407

<  7 <  7 <  7 408

<  7 <  7 <  7 409

> 25 > 25 > 25 410

< 25 > 25 < 25 411

> 25 > 25 > 25 412

<  7 > 25 > 25 413

> 25 > 25 > 25 414

> 25 > 25 > 25 415

<  7 > 25 > 25 416

<  7 > 25 <  7 417

<  7 > 25 <  7 418

<  7 <  7 <  7 419

<  7 <  7 <  7 420

<  7 <  7 <  7 421

> 25 > 25 > 25 422

> 25 > 25 > 25 423

> 25 > 25 > 25 424

< 25 > 25 < 25 425

<  7 <  7 <  7 426

< 25 > 25 < 25 427

> 25 > 25 > 25 428

> 25 > 25 > 25 429

<  7 > 25 <  7 430

< 25 > 25 < 25 431

> 25 > 25 > 25 432

<  7 > 25 <  7 433

<  7 > 25 < & 434

> 25 > 25 > 25 435

> 25 > 25 > 25 436

<  7 > 25 <  7 437

<  7 > 25 <  7 438

> 25 > 25 > 25 439

> 25 > 25 > 25 440

> 25 > 25 < 25 441

> 25 > 25 > 25 442

<  7 < 25 <  7 443

<  7 < 25 <  7 444

<  7 < 25 <  7 445

<  7 <  7 <  7 446

<  7 <  7 <  7 447

<  7 <  7 <  7 448

<  7 > 25 < 25 449

> 25 > 25 > 25 450

> 25 > 25 > 25 451

<  7 > 25 <  7 452

<  7 > 25 <  7 453

<  7 <  7 <  7 454

<  7 <  7 <  7 455

<  7 <  7 <  7 456

<  7 <  7 <  7 457

<  7 <  7 <  7 458

<  7 <  7 <  7 459

> 25 > 25 > 25 460

<  7 <  7 <  7 461

<  7 <  7 <  7 462

> 25 > 25 > 25 463

= 25 > 25 = 25 464

<  7 > 25 <  7 465

<  7 < 25 <  7 466

> 25 > 25 < 25 467

> 25 > 25 > 25 468

= 25 > 25 > 25 469

<  7 > 25 <  7 470

> 25 > 25 > 25 471

> 25 <  7 472

< 25 > 25 < 25 473

<  7 < 25 <  7 474

<  7 < 25 <  7 475

<  7 <  7 <  7 476

> 25 > 25 < 25 477

<  7 > 25 <  7 478

> 25 > 25 > 25 479

> 25 > 25 < 25 480

> 25 > 25 > 25 481

> 25 > 25 > 25 482

<  7 <  7 <  7

EXAMPLE 33

This example demonstrates the lack of acute in vivo toxicity in mice forsome antibacterial compounds of the invention. Solutions of compounds in10% w/v hydroxypropyl-β-cyclodextrin in 0.9% w/v saline were prepared.Doses of 40 mg/kg or 120 mg/kg of each compound were administered tomice (5 mice/compound/dose) via intraperitoneal injections. the micewere observed for seven days.

Mice Surviving Compound Dose on Day 7 # (mg/kg) (%) 193  40 100 193 120100 316  40  80 316 120  0 420  40 100 420 120 100 379  40  40 379 120 0 419  40  40 419 120  0 417  40 100 417 120 100 380  40 100 380 120  0418  40 100 418 120  0 307  40 100 307 120 100 447  40  80 447 120 100461  40 100 461 120 100 474  40 100 474 120 100 342  40 100 342 120 100107  40 100 107 120  0 359  40 100 359 120 100

EXAMPLE 34

The example demonstrates the in vivo efficacy of an antibacterialcompound of the invention for treating a methicillin-resistantStaphylococcus aureus infection. An intraperitoneal (ip) mouse infectionmodel known in the art was utilized. A group of 10 female mice (5 testanimals and 5 control animals) was inoculated ip withmethicillin-resistant Staphylococcus aureus. One hour after bacterialinoculation, five of the animals were given an interperitoneal injectionof 40 mg/kg 61 as a 7 mg/mL solution in 10% w/vhydroxypropyl-β-cyclodextrin in 0.9% w/v saline After twenty-four hoursall five animals that received 61 were alive, but four of the untreatedanimals had expired. After seven days, four of the treated animals werestill alive.

All of the references cited in this document are hereby incorporated byreference.

Equivalents

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

We claim:
 1. A compound represented by the general formula 1:

wherein A and B represent fused benzo rings; X represents N; Yrepresents NR; R, R₂, and R₃, for each occurrence, independentlyrepresent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl,silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl,phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride,silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone,aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal,ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate,epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide,thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; R₁ representshydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy,amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl,phosphonate, phosphine, carbonyl, carboxamide, anhydride, silyl,thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde,ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amineoxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide,hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate,urea, thiourea, or —(CH₂)_(m)—R₈₀; R₄, for each occurrence,independently represent halogen, alkyl, alkenyl, alkynyl, hydroxyl,alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide,phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide,anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl,ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine,acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; R₅, foreach occurrence, independently represents halogen, alkyl, alkenyl,alkynyl, hydroxyl, silyloxy, amino, sulfhydryl, alkylthio, imine, amide,phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide,anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl,ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine,acetal, ketal, amine oxide, azide, aziridine, carbamate, epoxide,hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate,urea, thiourea, or —(CH₂)_(m)—R₈₀; A may be unsubstituted or substitutedwith R₄ any number of times up to the limitations imposed by stabilityand the rules of valence; B is substituted with at least one instance ofR₅, but in no case more than the maximum number of instances of R₅allowed by the limitations imposed by stability and the rules ofvalence; R₈₀ represents an unsubstituted or substituted aryl, acycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle; n is aninteger in the range 1 to 8 inclusive; and m is an integer in the range0 to 8 inclusive.
 2. The compound of claim 1, wherein R₁ represents—C(Z)N(R)(R′—NHR); Z represents O, S, or NR; and R′ represents alkylene,alkenylene, alkynylene, arylene, or heteroarylene.
 3. The compound ofclaim 2, wherein R′ represents an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, aryl, or heteroaryl.
 4. The compound of claim 3,wherein R′ represents a cycloalkyl.
 5. The compound of claim 2, whereinR₂ and R₃, independently for each occurrence, represent H or analiphatic group; R₄, independently for each occurrence, represents C₁-C₆alkyl, 1-alkenyl, 1-alkynyl, aryl, —OR, —OCF₃, —OC(R)₂OR, —C(R)₂OR,—CO₂R, halogenated C₁-C₆ alkyl, or halogen; and R₅, independently foreach occurrence, represents C₁-C₆ alkyl, halogenated C₁-C₆ alkyl, orhalogen.
 6. The compound of claim 5, wherein R₂ and R₃ independently foreach occurrence represent H, a C₁-C₆ alkyl or aryl.
 7. The compound ofclaim 7, wherein the instance of R in Y represents H, alkyl,alkylsulfonyl, arylsulfonyl, or —(CH₂)_(m)—R₈₀.
 8. The compound of claim5, 6 or 7, wherein of R₄ occurs at least once and represents a halogenor a 1-alkynyl.
 9. The compound of claim 8, wherein R₄ occurs at leastonce and represents —CCR₆₀; and R₆₀ represents hydrogen, halogen, alkyl,alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, aminoalkyl,alkylamino, sulfhydryl, alkylthio, imine, amide, carbonyl, carboxyl,silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, heteroalkyl,nitrile, amidine, amine oxide, aryl, heteroaryl, carbamate, imide,oxime, sulfonamide, thioamide, urea, or —(CH₂)_(m)—R₈₀.
 10. The compoundof claim 5, 6 or 7, wherein R₅ occurs at least once and represents ahalogen.
 11. The compound of claim 9, wherein R₅ occurs at least onceand represents a halogen.
 12. The compound of claim 1, wherein theinstance of R in Y represents H, alkyl, alkylsulfonyl, arylsulfonyl, or—(CH₂)_(m)—R₈₀.
 13. The compound of claim 8, having a minimum inhibitoryconcentration (MIC) less than 10 μg/mL against at least oneGram-positive bacterium.
 14. The compound of claim 5 or 6, having aminimum inhibitory concentration (MIC) less than 10 μg/mL against atleast one Gram-positive bacterium.
 15. The compound of claim 10, havinga minimum inhibitory concentration (MIC) less than 10 μg/mL against atleast one Gram-positive bacterium.
 16. The compound of claim 1, whereinR₁ represents halogen, —C(Z)N(R)₂, —S(Z)₂N(R)₂, or —P(Z)₂N(R)₂; Zindependently for each occurrence represents (R)₂, O, S, or NR; and Rfor each occurrence, independently represents hydrogen, halogen, alkyl,alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl,alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl,carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl,arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl,nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl,heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R₈₀.
 17. The compound of claim 16, wherein R₁ represents—C(Z)N(R)₂.
 18. The compound of claim 16, wherein R₁ represents halogen,or —C(Z)N(R)₂.
 19. The compound of claim 16, wherein R₂ and R₃,independently for each occurrence, represent H or an aliphatic group;and R₄, independently for each occurrence, represents C₁-C₆ alkyl,1-alkenyl, 1-alkynyl, aryl, —OR, —OCF₃, —OC(R)₂OR, —C(R)₂OR, —CO₂R,halogenated C₁-C₆ alkyl or halogen.
 20. The compound of claim 19,wherein R₂ and R₃ independently for each occurrence represent H, a C₁-C₆alkyl or aryl.
 21. The compound of claim 16, 17, 18, 19, 20 or 24,wherein R₄ occurs at least once and represents a halogen or a 1-alkynyl.22. The compound of claim 21, wherein R₄ occurs at least once andrepresents —CCR₆₀; and R₆₀ represents hydrogen, halogen, alkyl, alkenyl,alkynyl, hydroxyl, alkoxyl, silyloxy, amino, aminoalkyl, alkylamino,sulfhydryl, alkylthio, imine, amide, carbonyl, carboxyl, silyl,thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, heteroalkyl,nitrile, amidine, amine oxide, aryl, heteroaryl, carbamate, imide,oxime, sulfonamide, thioamide, urea, or —(CH₂)_(m)—R₈₀.
 23. The compoundof claim 22, wherein R₅ occurs at least once and represents a halogen.24. The compound of claim 16, wherein the instance of R in Y representsH, alkyl, alkylsulfonyl, arylsulfonyl, or —(CH₂)_(m)—R₈₀.
 25. Thecompound of claim 16, 19, 20 or 24, wherein R₅ independently for eachoccurrence represents C₁-C₆ alkyl, halogenated C₁-C₆ alkyl, halogen,—C(O)N(R)₂, —CN, —OH, —O₂C-aryl, or —O₂C-alkyl.
 26. The compound ofclaim 25, wherein R₅ occurs at least once and represents a halogen,halogenated alkyl, —C(O)N(R)₂, —CN, —OH, —O₂C-aryl, or —O₂C-alkyl. 27.The compound of claim 25, having a minimum inhibitory concentration(MIC) less than 10 μg/mL against at least one Gram-positive bacterium.28. The compound of claim 19 or 20, having a minimum inhibitoryconcentration (MIC) less than 10 μg/mL against at least oneGram-positive bacterium.
 29. The compound of claim 21, having a minimuminhibitory concentration (MIC) less than 10 μg/mL against at least oneGram-positive bacterium.
 30. The compound of claim 1, wherein R₁represents a hydrogen.
 31. The compound of claim 30, wherein R₂ and R₃independently for each occurrence represent H or an aliphatic group; andR₄ independently for each occurrence represents C₁-C₆ alkyl, 1-alkenyl,1-alkynyl, aryl, —OR, —OCF₃, —OC(R)₂OR, —C(R)₂OR, —CO₂R, halogenatedC₁-C₆ alkyl, or halogen.
 32. The compound of claim 30, wherein R₂ and R₃independently for each occurrence represent H, a C₁-C₆ alkyl or aryl.33. The compound of claim 31 or 22, wherein R₄ occurs at least once andrepresents a halogen or a 1-alkynyl.
 34. The compound of claim 33,wherein R₄ occurs at least once and represents —CCR₆₀; and R₆₀represents hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl,alkoxyl, silyloxy, amino, aminoalkyl, alkylamino, sulfhydryl, alkylthio,imine, amide, carbonyl, carboxyl, silyl, thioalkyl, alkylsulfonyl,arylsulfonyl, selenoalkyl, heteroalkyl, nitrile, amidine, amine oxide,aryl, heteroaryl, carbamate, imide, oxime, sulfonamide, thioamide, urea,or —(CH₂)_(m)—R₈₀.
 35. The compound of claim 30 or 31, wherein R₅independently for each occurrence represents C₁-C₆ alkyl, halogenatedC₁-C₆ alkyl, halogen, —C(O)N(R)₂, —CN, —OH, —O₂C-aryl, or —O₂C-alkyl.36. The compound of claim 35, wherein R₅ occurs at least once andrepresents a halogen, halogenated alkyl, —C(O)N(R)₂, —CN, —OH,—O₂C-aryl, or —O₂C-alkyl.
 37. The compound of claim 1, wherein R₄ occursat least once and represents at least one 1-alkynyl group.
 38. Thecompound of claim 1, having a minimum inhibitory concentration (MIC)less than 10 μg/mL against at least one Gram-positive bacterium.
 39. Thecompound of claim 38, wherein the bacterium is selected from the groupconsisting of Staphylococcus spp and Enterococcus spp.
 40. The compoundof claim 38, having a therapeutic index in primates of at least 10 forthe inhibition of infection by at least one Gram-positive bacterium. 41.A compound represented by general formula 2:

wherein R, R_(a), R₃, R₁ , and R₂′, for each occurrence, independentlyrepresent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl,silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl,phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride,silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone,aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal,ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate,epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide,thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; R₄, and R₅, for eachoccurrence, independently represent halogen, alkyl, alkenyl, alkynyl,hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine,amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine,amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; Trepresents a covalent linker; the B-ring of the 2-quinolinyl moiety maybe unsubstituted, or substituted between one and four times inclusive byR₄; the B-ring of the 3-indolyl moiety is substituted with between oneand four instances of R₅; R₈₀ represents an aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle; and m is an integer in therange 0 to 8 inclusive.
 42. The compound of claim 41, wherein Trepresents a cyclic, branched or straight chain aliphatic group, 2-10bonds in length.
 43. The compound of claim 42, wherein T represents acycloalkyl group.
 44. The compound of claim 41, wherein R₂′ and R₃independently for each occurrence represent H or an aliphatic group; R₄independently for each occurrence represents C₁-C₆ alkyl, 1-alkenyl,1-alkynyl, aryl, —OR, —OCF₃, —OC(R)₂OR, —C(R)₂OR, —CO₂R, halogenatedC₁-C₆ alkyl, or halogen; and R₅ independently for each occurrencerepresents C₁-C₆ alkyl, halogenated C₁-C₆ alkyl, or halogen.
 45. Thecompound of claim 44, wherein R₂′ and R₃ independently for eachoccurrence represent H, C₁-C₆ alkyl or aryl.
 46. The compound of claim45, wherein R₂′ and R₃ independently for each occurrence represent H orMe.
 47. The compound of claim 46, wherein R, R_(a) and R′₁ independentlyfor each occurrence represent H, alkyl, alkylsulfonyl, arylsulfonyl, or—(CH₂)_(m)—R₈₀; wherein R₈₀ represents an aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle; and m is an integer in therange 0 to 8 inclusive.
 48. The compound of claim 41, 44, 45, 46 or 47,wherein R₄ occurs at least once and represents, independently for eachoccurrence, halogen, a 1-alkynyl group or a trihalogenated methyl group.49. The compound of claim 48, wherein R₄ occurs at least once andrepresents a 1-alkynyl group.
 50. The compound of claim 48, wherein R₄occurs at least once and represents a trihalogenated methyl group. 51.The compound of claim 48, wherein R₅ occurs at least once and representsa halogen.
 52. The compound of claim 48, wherein R₅ occurs at least onceand represents a halogenated C₁-C₆ alkyl group.
 53. The compound ofclaim 41, 44, 45, 46 or 47, wherein R₅ occurs at least once andrepresents a halogen.
 54. The compound of claim 41, 44, 45, 46 or 47,wherein R₅ occurs at least once and represents a halogenated C₁-C₆ alkylgroup.
 55. The compound of claim 48, having a minimum inhibitoryconcentration (MIC) less than 10 μg/mL against at least oneGram-positive bacterium.
 56. The compound of claim 41, 44, 45, 46 or 47,having a minimum inhibitory concentration (MIC) less than 10 μg/mLagainst at least one Gram-positive bacterium.
 57. A compound representedby the following general formula:

wherein R₃, R₅, R₆, R₇, R₈, R₂₁, R₂₂, R₁′, R₂′, R₄′, R₅′, R₆′, and R₇′,for each occurrence, independently represent hydrogen, halogen, alkyl,alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl,alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl,carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl,arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl,nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl,heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R₈₀; at least one member of the group consisting of R₄′, R₅′,R₆′, and R₇′ is not hydrogen, R₈₀ represents an aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle; and m is an integer in therange 0 to 8 inclusive.
 58. The compound of claim 57, wherein R₂′ and R₃independently for each occurrence represent H or an aliphatic group; R₅,R₆, R₇ and R₈ independently for each occurrence represent H, C₁-C₆alkyl, 1-alkenyl, 1-alkynyl, aryl, —OR, —OCF₃, —OC(R)₂OR, —C(R)₂OR,—CO₂R, halogenated C₁-C₆ alkyl, or halogen; R represents, independentlyfor each occurrence, hydrogen, halogen, alkyl, alkenyl, alkynyl,hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine,amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine,amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or (CH₂)_(m)—R₈₀; R₁′represents H, alkyl, aryl, p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or—(CH₂)_(n)N(R)₂; wherein n is an integer in the range 1 to 6 inclusive;R₄′, R₅′, R₆′ and R₇′ independently for each occurrence represent H,C₁-C₆ alkyl, halogenated C₁-C₆ alkyl, or halogen; and R₂₁ and R₂₂independently for each occurrence represent H, alkyl, aryl, or—(CH₂)_(m)—R₈₀, or R₂₁ and R₂₂ taken together with N represent aheterocycle comprising from 4 to 8 members inclusive, with the provisothat R₂₁ and R₂₂ are selected such that N(R₂₁)R₂₂ comprises at least oneprimary or secondary amine.
 59. The compound of claim 58, wherein R₂′and R₃ independently for each occurrence represent H, C₁-C₆ alkyl, oraryl.
 60. The compound of claim 58, wherein R₂′ and R₃ independently foreach occurrence represent H or —CH₃.
 61. The compound of claim 59,wherein R₅, R₆, R₇ and R₈ independently for each occurrence represent H,halogen, trihalogenated methyl or —CCR₆₀, and R₆₀ represents hydrogen,halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino,nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate,phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl,alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester,heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide,aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)-R₈₀.
 62. The compound of claim 57, 58, 59, 60 or 61, whereinR₄′, R₅′, R₆′ and R₇′ independently for each occurrence represent H,halogen, or a halogenated alkyl.
 63. The compound of claim 57, 58, 59,60 or 61, wherein R₂₁ and R₂₂ independently for each occurrencerepresent H, —(CH₂)_(n)NH(R₁′), ortho-CH₂C₆H₄CH₂NH(R₁′),meta-CH₂C₆H₄CH₂NH(R₁′), or para-CH₂C₆H₄CH₂NH(R₁′), ortho-CH₂C₆H₄O(R₁′),meta-CH₂C₆H₄O(R₁′), or para-CH₂C₆H₄O(R₁′), ortho-CH₂C₆H₄OMe,meta-CH₂C₆H₄OMe, or para-CH₂C₆H₄OMe, ortho-, meta-, or para-CH₂C₆H₄OH,(2-benzimidazolyl)CH₂—, 2-methoxyphenyl, 3-methoxyphenyl, or4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, or 4-hydroxyphenyl,or 2((R₁′)aminomethyl)cyclohexylmethyl,3((R₁′)aminomethyl)cyclohexylmethyl, or4-((R₁′)aminomethyl)cyclohexylmethyl; wherein n is an integer in therange 1 to 6 inclusive.
 64. The compound of claim 57, 58, 59, 60 or 61,having a minimum inhibitory concentration (MIC) less than 10 μg/mLagainst at least one Gram-positive bacterium.
 65. The compound of claim64, having a minimum inhibitory concentration (MIC) less than 1 μ/mLagainst at least one Gram-positive bacterium.
 66. The compound of claim64, having a minimum inhibitory concentration (MIC) less than 0.1 μg/mLagainst at least one Gram-positive bacterium.
 67. The compound of claim64, having a therapeutic index in primates of at least 10 for theinhibition of infection by at least one Gram-positive bacterium.
 68. Thecompound represented by general formula 3:

wherein R₃, R₁′, and R₂′, for each occurrence, independently representhydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy,amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl,phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride,silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone,aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal,ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate,epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide,thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; R₄, for eachoccurrence, independently represent halogen, alkyl, alkenyl, alkynyl,hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine,amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine,amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; R₅, foreach occurrence, independently represents halogen, alkyl, alkenyl,alkynyl, hydroxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine,amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine,amidine, acetal, ketal, amine oxide, azide, aziridine, carbamate,epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide,thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; the B-ring of the2-quinolinyl moiety may be unsubstituted, or substituted between one andfour times inclusive by R₄; the B-ring of the 3-indolyl moiety issubstituted with between one and four instances of R₅; R₈₀ represents anaryl, a cycloalkyl, a cycloalkenyl, a heterocycle , or a polycycle; andm is an integer in the range 0 to 8 inclusive.
 69. The compound of claim68, wherein R₁′ represents H, alkyl, aryl, Me, p-toluenesulfonyl,—(CH₂)_(n)N(Phth), or —(CH₂)_(n)N(R)₂; wherein n is an integer in therange 1 to 6 inclusive; R represents, independently for each occurrence,hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy,amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl,phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride,silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone,aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal,ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate,epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide,thiocarbamate, urea, thiourea, or (CH₂)_(m)—R₈₀; R₂′ and R₃independently for each occurrence represent H or an aliphatic group; R₄independently for each occurrence represents C₁-C₆ alkyl, 1-alkenyl,1-alkynyl, aryl, —OR, —OCF₃, —OC(R)₂OR, —C(R)₂OR, —CO₂R, halogenatedC₁-C₆ alkyl, or halogen; and R₅ independently for each occurrencerepresents C₁-C₆ alkyl, halogenated C₁-C₆ alkyl, halogen, —C(O)N(R)₂,—CN, —NO₂, —OH, —O₂Caryl, or —O₂Calkyl.
 70. The compound of claim 69,wherein R₂′ and R₃ independently for each occurrence represent H, C₁-C₆alkyl, or aryl.
 71. The compound of claim 70, wherein R₂′ and R₃independently for each occurrence represent H or —CH₃.
 72. The compoundof claim 68, 69 or 70, wherein R₄ independently for each occurrencerepresents a halogen, trihalogenated methyl or —CCR₆₀, and R₆₀represents hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl,alkoxyl, silyloxy, amino, aminoalkyl, alkylamino, sulfhydryl, alkylthio,imine, amide, carbonyl, carboxyl, silyl, thioalkyl, alkylsulfonyl,arylsulfonyl, selenoalkyl, heteroalkyl, nitrile, amidine, amine oxide,aryl, heteroaryl, carbamate, imide, oxime, sulfonamide, thioamide, urea,or —(CH₂)_(m)—R₈₀.
 73. The compound of claim 68, 69 or 70, wherein R₅independently for each occurrence represents C₁-C₆ alkyl, halogenatedC₁-C₆ alkyl, halogen, —C(O)N(R)₂, —CN, —NO₂, —OH, —O₂Caryl, or—O₂Calkyl.
 74. The compound of claim 73, wherein R₅ independently foreach occurrence represents a halogen, a trihalogenated methyl,—C(O)N(R)₂, —CN, —NO₂, —OH, —OR, —O₂Caryl, or —O₂Calkyl.
 75. Thecompound of claim 68, 69, 70 or 71, having a minimum inhibitoryconcentration (MIC) less than 10 μg/mL against at least oneGram-positive bacterium.
 76. The compound of claim 75, having a minimuminhibitory concentration (MIC) less than 1 μg/mL against at least oneGram-positive bacterium.
 77. The compound of claim 75, having a minimuminhibitory concentration (MIC) less than 0.1 μg/mL against at least oneGram-positive bacterium.
 78. The compound of claim 75, having atherapeutic index in primates of at least 10 for the inhibition ofinfection by at least one Gram-positive bacterium.
 79. The compoundrepresented by the following general structure:

wherein R₂′ and R₃ independently for each occurrence represent H, C₁-C₆alkyl, or aryl; R₅, R₆, R₇, and R₈ independently for each occurrencerepresent H, C₁-C₆ alkyl, 1-alkenyl, 1-alkynyl, aryl, —C(O)N(R)₂,halogenated C₁-C₆ alkyl, or halogen; R represents, independently foreach occurrence, hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl,alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide,phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide,anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl,ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine,acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; R₁′represents H, alkyl, aryl, Me, or p-toluenesulfonyl; R₄′, R₅′, R₆′ andR₇′ independently for each occurrence represent H, C₁-C₆ alkylhalogenated C₁-C₆ alkyl, halogen, —C(O)NR₂, —CN, —NO₂, —OH, —O₂Caryl, or—O₂Calkyl; and at least one member of the group consisting of R₄′, R₅ ′,R₆′, and R₇′ is not hydrogen.
 80. The compound of claim 79, wherein R₂′and R₃ independently for each occurrence represent H, Me, or aryl; R₅,R₆, R₇, and R₈ independently for each occurrence represent H, a halogen,trihalogenated methyl, or —CCR₆₀, wherein R₆₀ represents hydrogen,halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino,aminoalkyl, alkylamino, sulfhydryl, alkylthio, imine, amide, carbonyl,carboxyl, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl,heteroalkyl, nitrile, amidine, amine oxide, aryl, heteroaryl, carbamate,imide, oxime, sulfonamide, thioamide, urea, or —(CH₂)_(m)—R₈₀; R₄′, R₅′,R₆′ and R₇′ independently for each occurrence represent H, a halogen, ahalogenated alkyl, —C(O)NR₂, —CN, —NO₂, —OH, —O₂Caryl, or —O₂Calkyl. 81.The compound of claim 80, wherein R₄′, R₅′, R₆′ and R₇′ independentlyfor each occurrence represent H, a halogen, or a trifluoromethyl group.82. The compound of claim 79, 80 or 81, having a minimum inhibitoryconcentration (MIC) less than 10 μg/mL against at least oneGram-positive bacterium.
 83. The compound of claim 82, having a minimuminhibitory concentration (MIC) less than 1 μg/mL against at least oneGram-positive bacterium.
 84. The compound of claim 82, having a minimuminhibitory concentration (MIC) less than 0.1 μg/mL against at least oneGram-positive bacterium.
 85. The compound of claim 82, having atherapeutic index in primates of at least 10 for the inhibition ofinfection by at least one Gram-positive bacterium.
 86. The compoundrepresented by general formula 4:

wherein R₂₀ represents H, Me, lower alkyl, halogen, —C(Z)N(R)₂,—S(Z)₂N(R)₂, or —P(Z)₂N(R)₂, wherein Z independently for each occurrencerepresents (R)₂, O, S, or NR; R, R₃, R₁′, and R₂′, for each occurrence,independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl,hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine,amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine,amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; R₄, foreach occurrence, independently represent halogen, alkyl, alkenyl,alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl,alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl,carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl,arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl,nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl,heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R₈₀; R₅, for each occurrence, independently representshalogen, alkyl, alkenyl, alkynyl, hydroxyl, silyloxy, amino, nitro,sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine,carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl,alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester,heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide,azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime,sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(n)—R₈₀; the B-ring of the 2-quinolinyl moiety may beunsubstituted, or substituted between one and four times inclusive byR₄; the B-ring of the 3-indolyl moiety is substituted with between oneand four instances of R₅; R₈₀ represents an aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle; n is an integer in therange 1 to 8 inclusive; and m is an integer in the range 0 to 8inclusive.
 87. The compound of claim 86, wherein R₂₀ represents halogen,or —C(Z)N(R)₂, and Z independently for each occurrence represents (R)₂,O, S, or NR.
 88. The compound of claim 86, wherein R₁′ represents H,alkyl, aryl, Me, or p-toluenesulfonyl; R₂′ and R₃ independently for eachoccurrence represent H, Me, C₁-C₆ alkyl, or aryl; R₄ independently foreach occurrence represents Me, C₁-C₆ alkyl, 1-alkenyl, 1-alkynyl, aryl,—OR, —OCF₃, —OCR₂OR, —CR₂OR, —CO₂R, halogenated C₁-C₆ alkyl, or halogen;and R₅ independently for each occurrence represents C₁-C₆ alkyl,halogenated C₁-C₆ alkyl, halogen, —C(O)NR₂, —CN, —NO₂, —OH, —O₂Caryl, or—O₂Calkyl.
 89. The compound of claim 88, wherein R₁′ represents H,alkyl, aryl, or p-toluenesulfonyl; and R₂′ and R₃ independently for eachoccurrence represent H, Me, or aryl.
 90. The compound of claim 89,wherein R₁′ represents H, or Me.
 91. The compound of claim 90, whereinR₂′ and R₃ independently for each occurrence represent H, or Me.
 92. Thecompound of claim 86, 87 or 88, wherein R₄ independently for eachoccurrence represents Me, a halogen, a halogenated alkyl, or —CCR₆₀, R₆₀represents hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl,alkoxyl, silyloxy, amino, aminoalkyl, alkylamino, sulfhydryl, alkylthio,imine, amide, carbonyl, carboxyl, silyl, thioalkyl, alkylsulfonyl,arylsulfonyl, selenoalkyl, heteroalkyl, nitrile, amidine, amine oxide,aryl, heteroaryl, carbamate, imide, oxime, sulfonamide, thioamide, urea,or —(CH₂)_(m)—R₈₀.
 93. The compound of claim 92, wherein R₄independently for each occurrence represents a halogen, or atrifluoromethyl group.
 94. The compound of claim 86, 87 or 88, whereinR₅ independently for each occurrence represents C₁-C₆ alkyl, halogenatedC₁-C₆ alkyl, halogen, —C(O)NR₂, —CN, —NO₂, —OH, —O₂Caryl, or —O₂Calkyl.95. The compound of claim 94, wherein R₅ independently for eachoccurrence represents a halogen, a halogenated alkyl, —C(O)NR₂, —CN,—NO₂, —OH, —OR, —O₂Caryl, or —O₂Calkyl.
 96. The compound of claim 86, 87or 88, having a minimum inhibitory concentration (MIC) less than 10μg/mL against at least one Gram-positive bacterium.
 97. The compound ofclaim 96, having a minimum inhibitory concentration (MIC) less than 1μg/mL against at least one Gram-positive bacterium.
 98. The compound ofclaim 96, having a minimum inhibitory concentration (MIC) less than 0.1μg/mL against at least one Gram-positive bacterium.
 99. The compound ofclaim 96, having a therapeutic index in primates of at least 10 for theinhibition of infection by at least one Gram-positive bacterium. 100.The compound represented by the following general formula:

wherein R₃, R₄, R₁′, R₂′, and R₆₀ for each occurrence, independentlyrepresent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl,silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl,phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride,silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone,aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal,ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate,epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide,thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; R₅, and R₇, for eachoccurrence, independently represent halogen, alkyl, alkenyl, alkynyl,hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine,amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine,amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; the B-ringof the 2-quinolinyl moiety may be unsubstituted beyond the alkynyl groupor substituted between one and three times inclusive by R₅; the B-ringof the 3-indolyl moiety may be unsubstituted or substituted between oneand four times inclusive by R₇; R₈₀ represents an aryl, a cycloalkyl, acycloalkenyl, a heterocycle , or a polycycle; and m is an integer in therange 0 to 8 inclusive.
 101. The compound of claim 99, wherein R₁′represents H, alkyl, aryl, Me, or p-toluenesulfonyl; R₂′, R₃, and R₄independently for each occurrence represent H, Me, C₁-C₆ alkyl, or aryl;R₅ independently for each occurrence represents Me, C₁-C₆ alkyl,1-alkenyl, 1-alkynyl, aryl, —OR, —OCF₃, —OCR₂OR, —CR₂OR, —CO₂R,halogenated C₁-C₆ alkyl, or halogen; R represents, independently foreach occurrence, hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl,alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide,phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide,anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl,ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine,acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; and R₇independently for each occurrence represents C₁-C₆ alkyl, halogenatedC₁-C₆ alkyl, halogen, —C(O)NR₂, —CN, —NO₂, —OH, —OR, —O₂Caryl, or—O₂Calkyl.
 102. The compound represented by the following generalstructure:

wherein Z independently for each occurrence represents (R)₂, O, S, orNR; R₅, R₇, and R₈ independently for each occurrence represent H, Me,C₁-C₆ alkyl, heteroalkyl, 1-alkenyl, 1-alkynyl, aryl, heteroaryl, —OR,—OCF₃, —OCR₂OR, —CR₂OR, —CO₂R, halogenated C₁-C₆ alkyl, or halogen; Rrepresents, independently for each occurrence, hydrogen, halogen, alkyl,alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl,alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl,carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl,arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl,nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl,heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R₈₀; R₆ is selected from the group comprising NHR, N(R)₂,1-piperidyl, 1-piperazinyl, 1-pyrrolidinyl, 2-phenylethylamino,4-morpholinyl, and 4-phenylmethyl-1-piperidyl; R₁′ represents H, alkyl,aryl, p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or —(CH₂)_(n)N(R)₂; whereinn is an integer in the range 1 to 6 inclusive; R₂′ and R₃ independentlyfor each occurrence represent H, Me, C₁-C₆ alkyl, or aryl; R₄′, R₅′, R₆′and R₇′ independently for each occurrence represent H, C₁-C₆ alkyl,halogenated C₁-C₆ alkyl, halogen, —C(O)NR₂, —CN, —NO₂, —OH, —OR,—O₂Caryl, or —O₂Calkyl; and R₂₁ and R₂₂ independently for eachoccurrence represent H, alkyl, heteroalkyl, aryl, heteroaryl,—(CH₂)_(m)—R₈₀, or —(CH₂)_(n)N(R₁′)₂, wherein n is an integer in therange 1 to 6 inclusive, ortho-, meta-, or para-CH₂C₆H₄CH₂N(R₁ ′)₂,ortho-, meta-, or para-C₆H₄CH₂N(R₁′)₂, ortho-, meta-, orpara-CH₂C₆H₄O(R₁′), ortho-, meta-, or para-CH₂C₆H₄OMe, ortho-, meta-, orpara-CH₂C₆H₄OH, (2-benzimidazolyl)CH₂—, 2-, 3-, or 4-(R₁′)Ophenyl, 2-,3-, or 4-methoxyphenyl, 2-, 3-, or 4-hydroxyphenyl, or 2-, 3-, or4-((R₁′)₂NCH₂)cyclohexylmethyl, or 2-, 3-, or 4-((R₁′)₂N)cyclohexylmethyl; or N(R₂₁)R₂₂ taken together represent aheterocycle comprising from 4 to 8 members inclusive.
 103. The compoundof claim 102, wherein R₂′ and R₃ independently for each occurrencerepresent H, C₁-C₆ alkyl, or aryl.
 104. The compound of claim 103,wherein R₂′ and R₃ independently for each occurrence go represent H,—CH₃, or phenyl.
 105. The compound of claim 102, 103 or 104, wherein R₅,R₇ and R₈ independently for each occurrence represent H, halogen, ortrihalogenated methyl.
 106. The compound of claim 102, 103 or 104,wherein R₄′, R₅′, R₆′ and R₇′ independently for each occurrencerepresent H, halogen, or a halogenated alkyl.
 107. The compound of claim106, wherein R₄′, R₅′, R₆′ and R₇′ independently for each occurrencerepresent H, halogen, or trifluoromethyl.
 108. The compound of claim102, 103 or 104, wherein R₂₁ and R₂₂ independently for each occurrencerepresent H, —(CH₂)_(n)NH(R₁′), ortho-CH₂C₆H₄CH₂NH(R₁′),meta-CH₂C₆H₄CH₂NH(R₁′), or para-CH₂C₆H₄CH₂NH(R₁′), ortho-CH₂C₆H₄O(R₁′),meta-CH₂C₆H₄O(R₁′), or para-CH₂C₆H₄O(R₁′), ortho-CH₂C₆H₄OMe,meta-CH₂C₆H₄OMe, or para-CH₂C₆H₄OMe, ortho-, meta-, or para-CH₂C₆H₄OH,(2-benzimidazolyl)CH₂—, 2-methoxyphenyl, 3-methoxyphenyl, or4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, or 4-hydroxyphenyl,or 2((R₁′)aminomethyl)cyclohexylmethyl,3((R₁′)aminomethyl)cyclohexylmethyl, or4-((R₁′)aminomethyl)cyclohexylmethyl; wherein n is an integer in therange 1 to 6 inclusive.
 109. The compound of claim 102, 103 or 104,wherein R₆ is selected from the group comprising NHR, N(R)₂,1-piperidyl, 1-piperazinyl, 1-pyrrolidinyl, 2-phenylethylamino,4-morpholinyl, and 4-phenylmethyl-1-piperidyl.
 110. The compound ofclaim 102, 103 or 104, having a minimum inhibitory concentration (MIC)less than 10 μg/mL against at least one Gram-positive bacterium. 111.The compound of claim 110, having a minimum inhibitory concentration(MIC) less than 1 μg/mL against at least one Gram-positive bacterium.112. The compound of claim 110, having a minimum inhibitoryconcentration (MIC) less than 0.1 μg/mL against at least oneGram-positive bacterium.
 113. The compound of claim 110, having atherapeutic index in primates of at least 10 for the inhibition ofinfection by at least one Gram-positive bacterium.
 114. The compoundrepresented by the following general structure:

wherein Z independently for each occurrence represents (R)₂, O, S, orNR; R represents, independently for each occurrence, hydrogen, halogen,alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro,sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine,carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl,alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester,heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide,aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R₈₀; R₅, R₇, and R₈ independently for each occurrencerepresent H, Me, C₁-C₆ alkyl, heteroalkyl, 1-alkenyl, 1-alkynyl, aryl,heteroaryl, —OR, —OCF₃, —OCR₂OR, —CR₂OR, —CO₂R, halogenated C₁-C₆ alkyl,or halogen; R₆ is selected from the group comprising NHR, N(R)₂,1-piperidyl, 1-piperazinyl, 1-pyrrolidinyl, 2-phenylethylamino,4-morpholinyl, and 4-phenylmethyl-1-piperidyl; R₁′ represents H, alkyl,aryl, p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or —(CH₂)_(n)N(R)₂; whereinn is an integer in the range 1 to 6 inclusive; R₂′ and R₃ independentlyfor each occurrence represent H, Me, C₁-C₆ alkyl, or aryl; R₄′, R₅′, R₆′and R₇′ independently for each occurrence represent H, C₁-C₆ alkyl,halogenated C₁-C₆ alkyl, halogen, —C(O)NR₂, —CN, —NO₂, —OH, —OR,—O₂Caryl, or —O₂Calkyl; and m and n are integers independently selectedfrom the range 1 to 4 inclusive.
 115. The compound of claim 114, whereinR₂′ and R₃ independently for each occurrence represent H, Me, or phenyl.116. The compound of claim 114 or 115, wherein R₅, R₇, and R₈independently for each occurrence represent H, Me, —OR, —OCF₃, —OCR₂OR,—CR₂OR, —CO₂R, a halogen, or a halogenated alkyl.
 117. The compound ofclaim 114 or 115, wherein R₅, R₇, and R₈ independently for eachoccurrence represent H, Me, a halogen, or trifluoromethyl.
 118. Thecompound of claim 114 or 115, wherein R₄′, R₅′, R₆′ and R₇′independently for each occurrence represent H, a halogen, a halogenatedalkyl, —C(O)NR₂, —CN, —NO₂, —OH, —OR, —O₂Caryl, or —O₂Calkyl.
 119. Thecompound of claim 114 or 115, wherein R₄′, R₅ ′, R₆′ and R₇′independently for each occurrence represent H, a halogen, atrifluoromethyl, —C(O)NR₂, —CN, —NO₂, —OH, —OR, —O₂Caryl, or —O₂Calkyl.120. The compound of claim 114 or 115, wherein R₆ is selected from thegroup comprising NHR, N(R)₂, 1-piperidyl, 1-piperazinyl, 1-pyrrolidinyl,2-phenylethylamino, 4-morpholinyl, and 4-phenylmethyl-1-piperidyl. 121.The compound of claim 114 or 115, having a minimum inhibitoryconcentration (MIC) less than 10 μg/mL against at least oneGram-positive bacterium.
 122. The compound of claim 121, having aminimum inhibitory concentration (MIC) less than 1 μg/mL against atleast one Gram-positive bacterium.
 123. The compound of claim 121,having a minimum inhibitory concentration (MIC) less than 0.1 82 g/mLagainst at least one Gram-positive bacterium.
 124. The compound of claim121, having a therapeutic index in primates of at least 10 for theinhibition of infection by at least one Gram-positive bacterium. 125.The compound represented by the following general structure:

wherein Z independently for each occurrence represents (R)₂, O, S, orNR; R represents, independently for each occurrence, hydrogen, halogen,alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro,sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine,carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl,alkylsulfonyl, arylsulfonyl selenoalkyl, ketone, aldehyde, ester,heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine, oxide,aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R₈₀; R₅ R, and R, independently for each occurrence representH, Me, C₁-C₆ alkyl, heteroalkyl, 1-alkenyl, 1-alkynyl, aryl, heteroaryl,—OR, —OCF₃, —OCR₂OR, —CR₂OR, —Co₂R, halogenated C₁-C₆ alkyl, or halogen;R₇ is selected from the group comprising NHR, N(R)₂, 1-piperidyl,1-piperazinyl, 1-pyrrolidinyl, 2-phenylethyl amino, 4-morpholinyl, and4-phenylmethyl-1-piperidyl; R₁′ represents H, alkyl, aryl,p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or —(CH₂)_(n)N(R)₂ wherein n is aninteger in the range 1 to 6 inclusive; R₂′ and R₃ independently for eachoccurrence represent H, Me, C₁-C₆ alkyl, or aryl; R₄′, R₅′, R₆′ and R₇′independently for each occurrence represent H, C₁-C₆ alkyl, halogenatedC₁-C₆ alkyl, halogen, —C(O)NR₂, —CN, —NO₂, —OH, —OR, —O₂Caryl, or—O₂Calkyl; and R₂₁ and R₂₂ independently for each occurrence representH, alkyl, heteroalkyl, aryl, heteroaryl, —(CH₂)_(m)—R₈₀, or—(CH₂)_(n)N(R₁′)₂, wherein n is an integer in the range 1 to 6inclusive, ortho-, meta-, or para-CH₂C₆H₄CH₂N(R₁′)₂, ortho-, meta-, orpara-C₆H₄CH₂N(R₁ ′)₂, ortho-, meta-, or para-CH₂C₆H₄O(R₁′), ortho-,meta-, or para-CH₂C₆H₄OMe, ortho-, meta-, or para-CH₂C₆H₄OH,(2-benzimidazolyl)CH₂—, 2-, 3-, or 4-(R₁′)Ophenyl, 2-, 3-, or4-methoxyphenyl, 2-, 3-, or 4-hydroxyphenyl, or 2-, 3-, or4-((R₁′)₂NCH₂)cyclohexylmethyl, or 2-, 3-, or4-((R₁′)₂N)cyclohexylmethyl; or N(R₂₁)R₂₂ taken together represent aheterocycle comprising from 4 to 8 members inclusive.
 126. The compoundof claim 125, wherein R₂′ and R₃ independently for each occurrencerepresent H, Me, or phenyl.
 127. The compound of claim 125, wherein R₅,R₆, and R₈ independently for each occurrence represent H, Me, —OR,—OCF₃, —OCR₂OR, —CR₂OR, —CO₂R, a halogen, or a halogenated alkyl. 128.The compound of claim 127, wherein R₅, R₆, and R₈ independently for eachoccurrence represent H, Me, a halogen, or trifluoromethyl.
 129. Thecompound of claim 125, wherein R₄′, R₅′, R₆′ and R₇′ independently foreach occurrence represent H, a halogen, a halogenated alkyl, —C(O)NR₂,—CN, —NO₂, —OH, —OR, —O₂Caryl, or —O₂Calkyl.
 130. The compound of claim129, wherein R₄′, R₅′, R₆′ and R₇′ independently for each occurrencerepresent H, a halogen, or a trifluoromethyl.
 131. The compound of claim125, wherein R₇ is selected from the group comprising NHR, N(R)₂,1-piperidyl, 1-piperazinyl, 1-pyrrolidinyl, 2-phenylethylamino,4-morpholinyl, and 4-phenylmethyl-1-piperidyl.
 132. The compound ofclaim 125, wherein R₂, and R₂₂ independently for each occurrencerepresent H, —(CH₂)_(n)NH(R₁′), ortho-CH₂C₆H₄CH₂NH(R₁′),meta-CH₂C₆H₄CH₂NH(R₁′), or para-CH₂C₆H₄CH₂NH(R₁′), ortho-CH₂C₆H₄O(R₁′),meta-CH₂C₆H₄O(R₁′), or para-CH₂C₆H₄O(R₁′), ortho-CH₂C₆H₄OMe,meta-CH₂C₆H₄OMe, or para-CH₂C₆H₄OMe, ortho-, meta-, or para-CH₂C₆H₄OH,(2-benzimidazolyl)CH₂—, 2-methoxyphenyl, 3-methoxyphenyl, or4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, or 4-hydroxyphenyl,or 2((R₁′)aminomethyl)cyclohexylmethyl,3((R₁′)aminomethyl)cyclohexylmethyl, or4-((R₁′)aminomethyl)cyclohexylmethyl; wherein n is an integer in therange 1 to 6 inclusive.
 133. The compound of claim 125, having a minimuminhibitory concentration (MIC) less than 10 μg/mL against at least oneGram-positive bacterium.
 134. The compound of claim 125, having aminimum inhibitory concentration (MIC) less than 1 μg/mL against atleast one Gram-positive bacterium.
 135. The compound of claim 125,having a minimum inhibitory concentration (MIC) less than 0.1 μg/mLagainst at least one Gram-positive bacterium.
 136. The compound of claim125, having a therapeutic index in primates of at least 10 for theinhibition of infection by at least one Gram-positive bacterium. 137.The compound represented by the following general formula:

wherein Z independently for each occurrence represents (R)₂, O, S, orNR; R represents, independently for each occurrence, hydrogen, halogen,alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro,sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine,carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl,alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester,heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide,aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R₈₀; R₅, R₆, and R₈ independently for each occurrencerepresent H, Me, C₁-C₆ alkyl, heteroalkyl, 1-alkenyl, 1-alkynyl, aryl,heteroaryl, —OR, —OCF₃, —OCR₂OR, —CR₂OR, -CO₂R, halogenated C₁-C₆ alkyl,or halogen; R₇ is selected from the group comprising NHR, N(R)₂,1-piperidyl, 1-piperazinyl, 1-pyrrolidinyl, 2-phenylethylamino,4-morpholinyl, and 4-phenylmethyl-1-piperidyl; R₁′ represents H, alkyl,aryl, p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or —(CH₂)_(n)N(R)₂; whereinn is an integer in the range 1 to 6 inclusive; R₂′ and R₃ independentlyfor each occurrence represent H, Me, C₁-C₆ alkyl, or aryl; R₄′, R₅′, R₆′and R₇′ independently for each occurrence represent H, C₁-C₆ alkyl,halogenated C₁-C₆ alkyl, halogen, —C(O)NR₂, —CN, —NO₂, —OH, —OR,—O₂Caryl, or-O₂Calkyl; and m and n are integers independently selectedfrom the range 1 to 4 inclusive.
 138. The compound of claim 137, whereinR₂′ and R₃ independently for each occurrence represent H, Me, or phenyl.139. The compound of claim 137 or 138, wherein R₅, R₆, and R₈independently for each occurrence represent H, Me, —OR, —OCF₃, —OCR₂OR,—CR₂OR, —CO₂R, a halogen, or a halogenated alkyl.
 140. The compound ofclaim 139, wherein R₅, R₆, and R₈ independently for each occurrencerepresent H, Me, a halogen, or trifluoromethyl.
 141. The compound ofclaim 137 or 138, wherein R₄′, R₅′, R₆′ and R₇′ independently for eachoccurrence represent H, a halogen, a halogenated alkyl, —C(O)NR₂, —CN,—NO₂, —OH, —OR, —O₂Caryl, or —O₂Calkyl.
 142. The compound of claim 141,wherein R₄′, R₅′, R₆′ and R₇′ independently for each occurrencerepresent H, a halogen, a trifluoromethyl, —C(O)NR₂, —CN, —NO₂, —OH,—OR, —O₂Caryl, or —O₂Calkyl.
 143. The compound of claim 137, wherein R₇is selected from the group comprising NHR, N(R)₂, 1-piperidyl,1-piperazinyl, 1-pyrrolidinyl, 2-phenylethylamino, 4-morpholinyl, and4-phenylmethyl-1-piperidyl.
 144. The compound of claim 137, having aminimum inhibitory concentration (MIC) less than pg/mL against at leastone Gram-positive bacterium.
 145. The compound of claim 137, having aminimum inhibitory concentration (MIC) less than 1 10 μg/mL against atleast one Gram-positive bacterium.
 146. The compound of claim 137,having a minimum inhibitory concentration (MIC) less than 0.1 μg/mLagainst at least one Gram-positive bacterium.
 147. The compound of claim137, having a therapeutic index in primates of at least 10 for theinhibition of infection by at least one Gram-positive bacterium. 148.The compound represented by the following general structure:

wherein Z independently for each occurrence represents (R)₂, O, S, orNR; R represents, independently for each occurrence, hydrogen, halogen,alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro,sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine,carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl,alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester,heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide,aryl heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R₈₀; R₅, R₆, and R₇ independently for each occurrencerepresent H, Me, C₁-C₆ alkyl, heteroalkyl, 1-alkenyl, 1-alkynyl, aryl,heteroaryl, —OR, —OCF₃, —OCR₂OR, —CR₂OR, —CO₂R, halogenated C₁-C₆ alkyl,or halogen; R₈ is selected from the group comprising NHR, N(R)₂,1-piperidyl, 1-piperazinyl, 1-pyrrolidinyl, 2-phenylethylamino,4-morpholinyl, and 4-phenylmethyl-1-piperidyl; R₁′ represents H, alkyl,aryl, p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or —(CH₂)_(n)N(R)₂; whereinn is an integer in the range 1 to 6 inclusive; R₂′ and R₃ independentlyfor each occurrence represent H, Me, C₁-C₆ alkyl, or aryl; R₄′, R₅′, R₆′and R₇′ independently for each occurrence represent H, C₁-C₆ alkyl,halogenated C₁-C₆ alkyl, halogen, —C(O)NR₂, —CN, —NO₂, —OH, —OR,—O₂Caryl, or-O₂Calkyl; and R₂₁ and R₂₂ independently for each occurrencerepresent H, alkyl, heteroalkyl, aryl, heteroaryl, —(CH₂)_(m)—R₈₀, or—(CH₂)_(n)N(R₁′)₂, wherein n is an integer in the range 1 to 6inclusive, ortho-, meta-, or para-CH₂C₆H₄CH₂N(R₁′)₂, ortho-, meta-, orpara-C₆H₄CH₂N(R₁′)₂, ortho-, meta-, or para-CH₂C₆H₄O(R₁′), ortho-,meta-, orpara-CH₂C₆H₄OMe, ortho-, meta-, or para-CH₂C₆H₄OH,(2-benzimidazolyl)CH₂—, 2-, 3-, or 4-(R₁′)Ophenyl, 2-, 3-, or4-methoxyphenyl, 2-, 3-, or 4-hydroxyphenyl, or 2-, 3-, or4-((R₁′)₂NCH₂)cyclohexylmethyl, or 2-, 3-, or4-((R₁′)₂N)cyclohexylmethyl; or N(R₂₁ )R₂₂ taken together represent aheterocycle comprising from 4 to 8 members inclusive.
 149. The compoundof claim 148, wherein R₂′ and R₃ independently for each occurrencerepresent H, Me, or phenyl.
 150. The compound of claim 148, wherein R₅,R₆, and R₇ independently for each occurrence represent H, Me, —OR,—OCF₃, —OCR₂OR, —CR₂OR, —CO₂R, a halogen, or a halogenated alkyl. 151.The compound of claim 150, wherein R₅, R₆, and R₇ independently for eachoccurrence represent H, Me, a halogen, or trifluoromethyl.
 152. Thecompound of claim 148, wherein R₄′, R₅′, R₆′ and R₇′ independently foreach occurrence represent H, a halogen, a halogenated alkyl, —C(O)NR₂,—CN, —NO₂, —OH, —OR, —O₂Caryl, or —O₂Calkyl.
 153. The compound of claim152, wherein R₄′, R₅′, R₆′ and R₇′ independently for each occurrencerepresent H, a halogen, or a trifluoromethyl.
 154. The compound of claim148, wherein R₈ is selected from the group comprising NHR, N(R)₂,1-piperidyl, 1-piperazinyl, 1-pyrrolidinyl, 2-phenylethylamino,4-morpholinyl, and 4-phenylmethyl-1-piperidyl.
 155. The compound ofclaim 148, wherein wherein R₂₁ and R₂₂ independently for each occurrencerepresent H, —(CH₂)_(n)NH(R₁′), ortho-CH₂C₆H₄CH₂NH(R₁′),meta-CH₂C₆H₄CH₂NH(R₁′), or para-CH₂C₆H₄CH₂NH(R₁′), ortho-CH₂C₆H₄O(R₁′),meta-CH₂C₆H₄O(R₁′), or para-CH₂C₆H₄O(R₁′), ortho-CH₂C₆H₄OMe,meta-CH₂C₆H₄OMe, or para-CH₂C₆H₄OMe, ortho-, meta-, or para-CH₂C₆H₄OH,(2-benzimidazolyl)CH₂—, 2-methoxyphenyl, 3-methoxyphenyl, or4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, or 4-hydroxyphenyl,or 2((R₁′)aminomethyl)cyclohexylmethyl,3((R₁′)aminomethyl)cyclohexylmethyl, or4-((R₁′)aminomethyl)cyclohexylmethyl, wherein n is an integer in therange 1 to 6 inclusive.
 156. The compound of claim 148, having a minimuminhibitory concentration (MIC) less than 10 μg/mL against at least oneGram-positive bacterium.
 157. The compound of claim 148, having aminimum inhibitory concentration (MIC) less than 1 μg/mL against atleast one Gram-positive bacterium.
 158. The compound of claim 148,having a minimum inhibitory concentration (MIC) less than 0.1 μg/mLagainst at least one Gram-positive bacterium.
 159. The compound of claim148, having a therapeutic index in primates of at least 10 for theinhibition of infection by at least one Gram-positive bacterium. 160.The compound represented by the following general formula:

wherein Z independently for each occurrence represents (R)₂, O, S, orNR; R represents, independently for each occurrence, hydrogen, halogen,alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro,sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine,carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl,alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester,heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide,aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R₈₀; R₅, R₆, and R₇ independently for each occurrencerepresent H, Me, C₁-C₆ alkyl, heteroalkyl, 1-alkenyl, 1-alkynyl, aryl,heteroaryl, —OR, —OCF₃, —OCR₂OR, —CR₂OR, —CO₂R, halogenated C₁-C₆ alkyl,or halogen; R₈ is selected from the group comprising NHR, N(R)₂,1-piperidyl, 1-piperazinyl, 1-pyrrolidinyl, 2-phenylethylamino,4-morpholinyl, and 4-phenylmethyl-1-piperidyl; R₁′ represents H, alkyl,aryl, p-toluenesulfonyl, —(CH₂)_(n)N(Phth), or —(CH₂)_(n)N(R)₂; whereinn is an integer in the range 1 to 6 inclusive; R₂′ and R₃ independentlyfor each occurrence represent H, Me, C₁-C₆ alkyl, or aryl; R₄′, R₅′, R₆′and R₇′ independently for each occurrence represent H, C₁-C₆ alkyl,halogenated C₁-C₆ alkyl, halogen, —C(O)NR₂, —CN, —NO₂, —OH, —OR,—O₂Caryl, or —O₂Calkyl; and m and n are integers independently selectedfrom the range 1 to 4 inclusive.
 161. The compound of claim 160, whereinR₂′ and R₃ independently for each occurrence represent H, Me, or phenyl.162. The compound of claim 160, wherein R₅, R₆, and R₇ independently foreach occurrence represent H, Me, —OR, —OCF₃, —OCR₂OR, —CR₂OR, —CO₂R, ahalogen, or a halogenated alkyl.
 163. The compound of claim 162, whereinR₅, R₆, and R₇ independently for each occurrence represent H, Me, ahalogen, or trifluoromethyl.
 164. The compound of claim 160, whereinR₄′, R₅′, R₆′ and R₇′ independently for each occurrence represent H, ahalogen, a halogenated alkyl, —C(O)NR₂, —CN, —NO₂, —OH, —OR, —O₂Caryl,or —O₂Calkyl.
 165. The compound of claim 164, wherein R₄′, R₅′, R₆′ andR₇′ independently for each occurrence represent H, a halogen, atrifluoromethyl, —C(O)NR₂, —CN, —NO₂, —OH, —OR, —O₂Caryl, or —O₂Calkyl.166. The compound of claim 160, wherein R₈ is selected from the groupcomprising NHR, N(R)₂, 1-piperidyl, 1-piperazinyl, 1-pyrrolidinyl,2-phenylethylamino, 4-morpholinyl, and 4-phenylmethyl-1-piperidyl. 167.The compound of claim 160, having a minimum inhibitory concentration(MIC) less than 10 μg/mL against at least one Gram-positive bacterium.168. The compound of claim 160, having a minimum inhibitoryconcentration (MIC) less than 1 μg/mL against at least one Gram-positivebacterium.
 169. The compound of claim 160, having a minimum inhibitoryconcentration (MIC) less than 0.1 μg/mL against at least oneGram-positive bacterium.
 170. The compound of claim 160, having atherapeutic index in primates of at least 10 for the inhibition ofinfection by at least one Gram-positive bacterium.
 171. A pharmaceuticalpreparation comprising, as an active ingredient for inhibition ofbacterial cell growth, a compound represented in the general formula 1:

wherein A and B represent fused benzo rings; X represents N; Yrepresents NR; R, R₁, R₂, and R₃, for each occurrence, independentlyrepresent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl,silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl,phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride,silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone,aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal,ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate,epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide,thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; R₄, for eachoccurrence, independently represent halogen, alkyl, alkenyl, alkynyl,hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine,amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine,amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; R₅, foreach occurrence, independently represents halogen, alkyl, alkenyl,alkynyl, hydroxyl, alkoxyl, silyloxy, amino, sulfhydryl, alkylthio,imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine,amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; A may beunsubstituted or substituted with R₄ any number of times up to thelimitations imposed by stability and the rules of valence; B issubstituted with at least one instance of R₅, but in no case more thanthe maximum number of instances of R₅ allowed by the limitations imposedby stability and the rules of valence; R₈₀ represents an unsubstitutedor substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or apolycycle; and m is an integer in the range 0 to 8 inclusive.
 172. Apreparation for topical application to a cutaneous or mucosal tissue,comprising, as an active ingredient for inhibition of bacterial cellgrowth on the tissue, a compound represented in the general formula 1:

wherein A and B represent fused benzo rings; X represents N; Yrepresents NR; R, R₁, R₂, and R₃, for each occurrence, independentlyrepresent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl,silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl,phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride,silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone,aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal,ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate,epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide,thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; R₄, for eachoccurrence, independently represent halogen, alkyl, alkenyl, alkynyl,hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine,amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine,amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; R₅, foreach occurrence, independently represents halogen, alkyl, alkenyl,alkynyl, hydroxyl, alkoxyl, silyloxy, amino, sulfhydryl alkylthio,imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine,amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamidethioamide, thiocarbamate, urea, thiourea, or —(CH₂)m—R₈₀; A may beunsubstituted or substituted with R₄ any number of times up to thelimitations imposed by stability and the rules of valence; B issubstituted with at least one instance of R₅, but in no case more thanthe maximum number of instances of R₅ allowed by the limitations imposedby stability and the rules of valence, R₈₀ represents an unsubstitutedor substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or apolycycle; and m is an integer in the range 0 to 8 inclusive.
 173. Thepreparation of claim 172, wherein the compound is formulated as a cream,lotion, ointment, liposome dispersion, emulsion, spray, pessary, foam orsolution for external application to a cutaneous or mucosal surface.174. The preparation of claim 172 or 173, wherein the compound isformulated for external application to corneal or dermal surfaces. 175.A method for inhibiting bacterial cell growth comprising contactingbacteria with a compound represented in the general formula 1:

wherein A and B represent fused benzo rings; X represents N; Yrepresents NR; R, R₁, R₂, and R₃, for each occurrence, independentlyrepresent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl,silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl,phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride,silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone,aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal,ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate,epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide,thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; R₄, for eachoccurrence, independently represent halogen, alkyl, alkenyl, alkynyl,hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine,amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine,amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; R₅, foreach occurrence, independently represents halogen, alkyl, alkenyl,alkynyl, hydroxyl, alkoxyl, silyloxy, amino, sulfhydryl, alkylthio,imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine,amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂m—R₈₀; A may beunsubstituted or substituted with R₄ any number of times up to thelimitations imposed by stability and the rules of valence; B issubstituted with at least one instance of R₅, but in no case more thanthe maximum number of instances of R₅ allowed by the limitations imposedby stability an the rules of valence; R₈₀ represents an unsubstituted orsubstituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle , or apolycycle; and m is an integer in the range 0 to 8 inclusive.
 176. Themethod of claim 175, wherein the bacteria is a Gram-positive bacteria.177. The method of claim 176, wherein bacteria is selected from thegroup consisting of Staphylococcus, Streptococcus, Micrococcus,Peptococcus, Peptostreptococcus, Enterococcus, Bacillus, Clostridium,Lactobacillus, Listeria, Erysipelothrix, Propionibacterium, Eubacterium,and Corynebacterium.
 178. The method of claim 175, wherein the bacteriais resistant to methicillin and/or vancomycin.
 179. The method of claim175 or 178, wherein the bacteria is selected from the group consistingof Staphylococcus spp and Enterococcus spp .
 180. The method of claim175, wherein the bacteria is contacted with the compound in vitro. 181.The method of claim 175, wherein the bacteria is contacted with thecompound in vivo.
 182. A method for treating or preventing bacterialinfection in an animal, or an external tissue surface thereof,comprising administering a pharmaceutical preparation of a compoundrepresented in the general formula 1:

wherein A and B represent fused benzo rings; X represents N; Yrepresents NR; R, R₁, R₂, and R₃, for each occurrence, independentlyrepresent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl,silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl,phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride,silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone,aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal,ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate,epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide,thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; R₄, for eachoccurrence, independently represent halogen, alkyl, alkenyl, alkynyl,hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine,amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine,amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; R₅, foreach occurrence, independently represents halogen, alkyl, alkenyl,alkynyl, hydroxyl, alkoxyl silyloxy, amino, sulfhydryl, alkylthio,imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine,amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; A may beunsubstituted or substituted with R₄ any number of times up to thelimitations imposed by stability and the rules of valence; B issubstituted with at least one instance of R₅, but in no case more thanthe maximum number of instances of R₅ allowed by the limitations imposedby stability and the rules of valence: R₈₀ represents an unsubstitutedor substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or apolycycle; and m is an integer in the range 0 to 8 inclusive.
 183. Themethod of claim 182, wherein the compound is administered to an animalsuffering from, or at risk of deveolping, bacteremia, a skin/woundinfection, a lower respiratory infection, endocarditis, or infection ofthe urinary tract.
 184. The method of claim 183, wherein the compound isadministered parenterally.
 185. The method of claim 184, wherein thecompound is administered intramuscularly, intravenously, subcutaneously,orally, topically or intranasally.
 186. The method of claim 183, whereinthe compound is administered systemically.
 187. The method of claim 182,wherein the compound is administered to a mammal.
 188. The method ofclaim 187, wherein the compound is administered to a primate.
 189. Themethod of claim 187, wherein the compound is administered to a human.190. A method for promoting weight gain in a livestock, comprisingadministering to the livestock a compound represented in the generalformula 1:

wherein A and B represent fused benzo rings; X represents N; Yrepresents NR; R, R₁, R₂, and R₃, for each occurrence, independentlyrepresent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl,silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl,phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride,silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone,aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal,ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate,epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide,thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; R₄, for eachoccurrence, independently represent halogen, alkyl, alkenyl, alkynyl,hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine,amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine,amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)—R₈₀; R₅, foreach occurrence, independently represents halogen, alkyl, alkenyl,alkynyl, hydroxyl, alkoxyl, silyloxy, amino, sulfhydryl, alkylthio,imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine,amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine,carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide,thioamide, thiocarbamate, urea, thiourea, or —(CH₂)_(m)-R₈₀; A may beunsubstituted or substituted with R₄ any number of times up to thelimitations imposed by stability and the rules of valence; B issubstituted with at least one instance of R₅, but in no case more thanthe maximum number of instances of R₅ allowed by the limitations imposedby stability and the rules of valence; R₈₀ represents an unsubstitutedor substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or apolycycle; and m is an integer in the range 0 to 8 inclusive.
 191. Themethod of claim 191, wherein the compound is administered systemically.192. The method of claim 191, wherein the compound is formulated infeedstuff fed to the livestock.